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Full text link : [https://en.wikipedia.org/wiki/Expression_quantitative_trait_loci https://en.wikipedia.org/wiki/Expression_quantitative_trait_loci]<br/>
== 2024.04.12 ==
In [https://en.wikipedia.org/wiki/Formal_language formal languages], which are used in [https://en.wikipedia.org/wiki/Mathematical_logic mathematical logic] and [https://en.wikipedia.org/wiki/Theoretical_computer_science theoretical computer science], a string is a finite sequence of [https://en.wikipedia.org/wiki/Symbol_(formal) symbols] that are chosen from a [https://en.wikipedia.org/wiki/Set_(mathematics) set] called an [https://en.wikipedia.org/wiki/Alphabet_(computer_science) alphabet].<br/> <br/> full text link : [https://en.wikipedia.org/wiki/String_(computer_science) https://en.wikipedia.org/wiki/String_(computer_science)]<br/> <br/> '''in structure'''<br/> '''String''' is a long flexible [https://en.wikipedia.org/wiki/Structure structure] made from [https://en.wikipedia.org/wiki/Fiber fibers] twisted together into a single strand, or from multiple such strands which are in turn twisted together. String is used to tie, bind, or hang other objects. It is also used as a material to make things, such as textiles, and in arts and crafts. String is a simple [https://en.wikipedia.org/wiki/Tool tool], and its use by humans is known to have been developed tens of thousands of years ago.<sup id="cite_ref-Evans_and_Webster_1-0">[https://en.wikipedia.org/wiki/String_(structure)#cite_note-Evans_and_Webster-1 [1]]</sup> In [https://en.wikipedia.org/wiki/Mesoamerica Mesoamerica], for example, string was invented some 20,000 to 30,000 years ago, and was made by twisting plant fibers together.<sup id="cite_ref-Evans_and_Webster_1-1">[https://en.wikipedia.org/wiki/String_(structure)#cite_note-Evans_and_Webster-1 [1]]</sup> String may also be a component in other tools, and in devices as diverse as weapons, musical instruments, and toys.<br/> <br/> full text link : [https://en.wikipedia.org/wiki/String_(structure) https://en.wikipedia.org/wiki/String_(structure)]
<br/> <br/> <br/> <br/> == 2024.04.19 == === P-value === In [https://en.wikipedia.org/wiki/Statistical_hypothesis_testing null-hypothesis significance testing], the '''π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/81eac1e205430d1f40810df36a0edffdc367af36>-value'''<sup id="cite_ref-2">[https://en.wikipedia.org/wiki/P-value#cite_note-2 [note 1]]</sup> is the probability of obtaining test results at least as extreme as the [https://en.wikipedia.org/wiki/Realization_(probability) result actually observed], under the assumption that the [https://en.wikipedia.org/wiki/Null_hypothesis null hypothesis] is correct.<sup id="cite_ref-3">[https://en.wikipedia.org/wiki/P-value#cite_note-3 [2]]</sup><sup id="cite_ref-ASA_4-0">[https://en.wikipedia.org/wiki/P-value#cite_note-ASA-4 [3]]</sup> A very small ''p''-value means that such an extreme observed [https://en.wikipedia.org/wiki/Outcome_(probability) outcome] would be very unlikely under the null hypothesis. Even though reporting ''p''-values of statistical tests is common practice in [https://en.wikipedia.org/wiki/Academic_publishing academic publications] of many quantitative fields, misinterpretation and [https://en.wikipedia.org/wiki/Misuse_of_p-values misuse of p-values] is widespread and has been a major topic in mathematics and [https://en.wikipedia.org/wiki/Metascience metascience].<sup id="cite_ref-5">[https://en.wikipedia.org/wiki/P-value#cite_note-5 [4]]</sup><sup id="cite_ref-6">[https://en.wikipedia.org/wiki/P-value#cite_note-6 [5]]</sup> In 2016, the American Statistical Association (ASA) made a formal statement that "''p''-values do not measure the probability that the studied hypothesis is true, or the probability that the data were produced by random chance alone" and that "a ''p''-value, or statistical significance, does not measure the size of an effect or the importance of a result" or "evidence regarding a model or hypothesis".<sup id="cite_ref-7">[https://en.wikipedia.org/wiki/P-value#cite_note-7 [6]]</sup> That said, a 2019 task force by ASA has issued a statement on statistical significance and replicability, concluding with: "''p''-values and significance tests, when properly applied and interpreted, increase the rigor of the conclusions drawn from data".<sup id="cite_ref-ASA2019_8-0">[https://en.wikipedia.org/wiki/P-value#cite_note-ASA2019-8 [7]]</sup><br/> <br/> In statistics, every conjecture concerning the unknown [https://en.wikipedia.org/wiki/Probability_distribution probability distribution] of a collection of random variables representing the observed data π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/68baa052181f707c662844a465bfeeb135e82bab> in some study is called a ''statistical hypothesis''. If we state one hypothesis only and the aim of the statistical test is to see whether this hypothesis is tenable, but not to investigate other specific hypotheses, then such a test is called a [https://en.wikipedia.org/wiki/Statistical_hypothesis_testing null hypothesis test]. As our statistical hypothesis will, by definition, state some property of the distribution, the [https://en.wikipedia.org/wiki/Null_hypothesis null hypothesis] is the default hypothesis under which that property does not exist. The null hypothesis is typically that some parameter (such as a correlation or a difference between means) in the populations of interest is zero. Our hypothesis might specify the probability distribution of π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/68baa052181f707c662844a465bfeeb135e82bab> precisely, or it might only specify that it belongs to some class of distributions. Often, we reduce the data to a single numerical statistic, e.g., π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/ec7200acd984a1d3a3d7dc455e262fbe54f7f6e0>, whose marginal probability distribution is closely connected to a main question of interest in the study. The ''p''-value is used in the context of null hypothesis testing in order to quantify the [https://en.wikipedia.org/wiki/Statistical_significance statistical significance] of a result, the result being the observed value of the chosen statistic π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/ec7200acd984a1d3a3d7dc455e262fbe54f7f6e0>.<sup id="cite_ref-9">[https://en.wikipedia.org/wiki/P-value#cite_note-9 [note 2]]</sup> The lower the ''p''-value is, the lower the probability of getting that result if the null hypothesis were true. A result is said to be ''statistically significant'' if it allows us to reject the null hypothesis. All other things being equal, smaller ''p''-values are taken as stronger evidence against the null hypothesis. Loosely speaking, rejection of the null hypothesis implies that there is sufficient evidence against it. As a particular example, if a null hypothesis states that a certain summary statistic π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/ec7200acd984a1d3a3d7dc455e262fbe54f7f6e0> follows the standard [https://en.wikipedia.org/wiki/Normal_distribution normal distribution] π(0,1),<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/56a1569ab3f65b7d30a222662aa537e7e4965344> then the rejection of this null hypothesis could mean that (i) the mean of π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/ec7200acd984a1d3a3d7dc455e262fbe54f7f6e0> is not 0, or (ii) the [https://en.wikipedia.org/wiki/Variance variance] of π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/ec7200acd984a1d3a3d7dc455e262fbe54f7f6e0> is not 1, or (iii) π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/ec7200acd984a1d3a3d7dc455e262fbe54f7f6e0> is not normally distributed. Different tests of the same null hypothesis would be more or less sensitive to different alternatives. However, even if we do manage to reject the null hypothesis for all 3 alternatives, and even if we know that the distribution is normal and variance is 1, the null hypothesis test does not tell us which non-zero values of the mean are now most plausible. The more independent observations from the same probability distribution one has, the more accurate the test will be, and the higher the precision with which one will be able to determine the mean value and show that it is not equal to zero; but this will also increase the importance of evaluating the real-world or scientific relevance of this deviation.<br/> <br/> full text link : [https://en.wikipedia.org/wiki/P-value https://en.wikipedia.org/wiki/P-value] === Log === In [https://en.wikipedia.org/wiki/Mathematics mathematics], the '''logarithm''' is the [https://en.wikipedia.org/wiki/Inverse_function inverse function] to [https://en.wikipedia.org/wiki/Exponentiation exponentiation]. That means that the logarithm of a number x to the '''base''' b is the [https://en.wikipedia.org/wiki/Exponent exponent] to which b must be raised to produce x. For example, since 1000 = 10<sup>3</sup>, the ''logarithm base'' 10<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/4ec811eb07dcac7ea67b413c5665390a1671ecb0> of 1000 is 3, or log<sub>10</sub>β(1000) = 3. The logarithm of x to ''base'' b is denoted as log<sub>''b''</sub>β(''x''), or without parentheses, log<sub>''b''</sub>β''x''. When the base is clear from the context or is irrelevant, such as in [https://en.wikipedia.org/wiki/Big_O_notation big O notation], it is sometimes written logβ''x''. The logarithm base 10 is called the ''decimal'' or [https://en.wikipedia.org/wiki/Common_logarithm ''common'' logarithm] and is commonly used in science and engineering. The [https://en.wikipedia.org/wiki/Natural_logarithm ''natural'' logarithm] has the number [https://en.wikipedia.org/wiki/E_(mathematical_constant) ''e'' β 2.718] as its base; its use is widespread in mathematics and [https://en.wikipedia.org/wiki/Physics physics], because of its very simple [https://en.wikipedia.org/wiki/Derivative derivative]. The [https://en.wikipedia.org/wiki/Binary_logarithm ''binary'' logarithm] uses base 2 and is frequently used in [https://en.wikipedia.org/wiki/Computer_science computer science]. Logarithms were introduced by [https://en.wikipedia.org/wiki/John_Napier John Napier] in 1614 as a means of simplifying calculations.<sup id="cite_ref-1">[https://en.wikipedia.org/wiki/Logarithm#cite_note-1 [1]]</sup> They were rapidly adopted by navigators, scientists, engineers, [https://en.wikipedia.org/wiki/Surveying surveyors], and others to perform high-accuracy computations more easily. Using [https://en.wikipedia.org/wiki/Mathematical_table#Tables_of_logarithms logarithm tables], tedious multi-digit multiplication steps can be replaced by table look-ups and simpler addition. This is possible because the logarithm of a [https://en.wikipedia.org/wiki/Product_(mathematics) product] is the [https://en.wikipedia.org/wiki/Summation sum] of the logarithms of the factors: logπβ‘(π₯π¦)=logπβ‘π₯+logπβ‘π¦,<br/> <img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/72599165912508b07108f2a840898022ed126148><br/> provided that b, x and y are all positive and ''b'' β 1. The [https://en.wikipedia.org/wiki/Slide_rule slide rule], also based on logarithms, allows quick calculations without tables, but at lower precision. The present-day notion of logarithms comes from [https://en.wikipedia.org/wiki/Leonhard_Euler Leonhard Euler], who connected them to the [https://en.wikipedia.org/wiki/Exponential_function exponential function] in the 18th century, and who also introduced the letter e as the base of natural logarithms.<sup id="cite_ref-2">[https://en.wikipedia.org/wiki/Logarithm#cite_note-2 [2]]</sup> [https://en.wikipedia.org/wiki/Logarithmic_scale Logarithmic scales] reduce wide-ranging quantities to smaller scopes. For example, the [https://en.wikipedia.org/wiki/Decibel decibel] (dB) is a [https://en.wikipedia.org/wiki/Units_of_measurement unit] used to express [https://en.wikipedia.org/wiki/Level_(logarithmic_quantity) ratio as logarithms], mostly for signal power and amplitude (of which [https://en.wikipedia.org/wiki/Sound_pressure sound pressure] is a common example). In chemistry, [https://en.wikipedia.org/wiki/PH pH] is a logarithmic measure for the [https://en.wikipedia.org/wiki/Acid acidity] of an [https://en.wikipedia.org/wiki/Aqueous_solution aqueous solution]. Logarithms are commonplace in scientific [https://en.wikipedia.org/wiki/Formula formulae], and in measurements of the [https://en.wikipedia.org/wiki/Computational_complexity_theory complexity of algorithms] and of geometric objects called [https://en.wikipedia.org/wiki/Fractal fractals]. They help to describe [https://en.wikipedia.org/wiki/Frequency frequency] ratios of [https://en.wikipedia.org/wiki/Interval_(music) musical intervals], appear in formulas counting [https://en.wikipedia.org/wiki/Prime_number prime numbers] or [https://en.wikipedia.org/wiki/Stirling's_approximation approximating] [https://en.wikipedia.org/wiki/Factorial factorials], inform some models in [https://en.wikipedia.org/wiki/Psychophysics psychophysics], and can aid in [https://en.wikipedia.org/wiki/Forensic_accounting forensic accounting]. The concept of logarithm as the inverse of exponentiation extends to other mathematical structures as well. However, in general settings, the logarithm tends to be a multi-valued function. For example, the [https://en.wikipedia.org/wiki/Complex_logarithm complex logarithm] is the multi-valued [https://en.wikipedia.org/wiki/Inverse_function inverse] of the complex exponential function. Similarly, the [https://en.wikipedia.org/wiki/Discrete_logarithm discrete logarithm] is the multi-valued inverse of the exponential function in finite groups; it has uses in [https://en.wikipedia.org/wiki/Public-key_cryptography public-key cryptography].<br/> <br/> full text link : [https://en.wikipedia.org/wiki/Logarithm https://en.wikipedia.org/wiki/Logarithm]<br/> === Likelihood === The '''likelihood function''' (often simply called the '''likelihood''') is the [https://en.wikipedia.org/wiki/Joint_probability_distribution joint] [https://en.wikipedia.org/wiki/Probability_mass_function probability mass] (or [https://en.wikipedia.org/wiki/Probability_density_function probability density]) of [https://en.wikipedia.org/wiki/Sample_(statistics) observed data] viewed as a function of the [https://en.wikipedia.org/wiki/Statistical_parameter parameters] of a [https://en.wikipedia.org/wiki/Statistical_model statistical model].<sup id="cite_ref-1">[https://en.wikipedia.org/wiki/Likelihood_function#cite_note-1 [1]]</sup><sup id="cite_ref-2">[https://en.wikipedia.org/wiki/Likelihood_function#cite_note-2 [2]]</sup><sup id="cite_ref-3">[https://en.wikipedia.org/wiki/Likelihood_function#cite_note-3 [3]]</sup> Intuitively, the likelihood function πΏ(πβ£π₯)<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/24a053912e70a2d35f7037375a39f9f7c3ea72d4> is the probability of observing data π₯<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/87f9e315fd7e2ba406057a97300593c4802b53e4> assuming π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/6e5ab2664b422d53eb0c7df3b87e1360d75ad9af> is the actual parameter. In [https://en.wikipedia.org/wiki/Maximum_likelihood_estimation maximum likelihood estimation], the [https://en.wikipedia.org/wiki/Arg_max arg max] (over the parameter π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/6e5ab2664b422d53eb0c7df3b87e1360d75ad9af>) of the likelihood function serves as a [https://en.wikipedia.org/wiki/Point_estimation point estimate] for π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/6e5ab2664b422d53eb0c7df3b87e1360d75ad9af>, while the [https://en.wikipedia.org/wiki/Fisher_information Fisher information] (often approximated by the likelihood's [https://en.wikipedia.org/wiki/Hessian_matrix Hessian matrix]) indicates the estimate's [https://en.wikipedia.org/wiki/Precision_(statistics) precision]. In contrast, in [https://en.wikipedia.org/wiki/Bayesian_statistics Bayesian statistics], parameter estimates are derived from the ''converse'' of the likelihood, the so-called [https://en.wikipedia.org/wiki/Posterior_probability posterior probability], which is calculated via [https://en.wikipedia.org/wiki/Bayes'_theorem Bayes' rule].<sup id="cite_ref-4">[https://en.wikipedia.org/wiki/Likelihood_function#cite_note-4 [4]]</sup><br/> The likelihood function, parameterized by a (possibly multivariate) parameter π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/6e5ab2664b422d53eb0c7df3b87e1360d75ad9af>, is usually defined differently for [https://en.wikipedia.org/wiki/Continuous_or_discrete_variable discrete and continuous] [https://en.wikipedia.org/wiki/Probability_distribution probability distributions] (a more general definition is discussed below). Given a probability density or mass function π₯β¦π(π₯β£π),<br/> <img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/442aa0f5b4796ef4a698a7e60aeb5006c8f020f2> where π₯<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/87f9e315fd7e2ba406057a97300593c4802b53e4> is a realization of the random variable π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/68baa052181f707c662844a465bfeeb135e82bab>, the likelihood function is πβ¦π(π₯β£π),<br/> <img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/e161b494cb41c7ddbb8d496ece959b776baba128><br/> often written<br/> πΏ(πβ£π₯).<br/> <img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/487868b15b5aaccd5bf67e86c197d68f37fadc8f> In other words, when π(π₯β£π)<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/0f01a2e70b1a8595be545c42562f00820bbff06d> is viewed as a function of π₯<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/87f9e315fd7e2ba406057a97300593c4802b53e4> with π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/6e5ab2664b422d53eb0c7df3b87e1360d75ad9af> fixed, it is a probability density function, and when viewed as a function of π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/6e5ab2664b422d53eb0c7df3b87e1360d75ad9af> with π₯<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/87f9e315fd7e2ba406057a97300593c4802b53e4> fixed, it is a likelihood function. In the [https://en.wikipedia.org/wiki/Frequentist_probability frequentist paradigm], the notation π(π₯β£π)<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/0f01a2e70b1a8595be545c42562f00820bbff06d> is often avoided and instead π(π₯;π)<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/79480c3540803bdda2613d69277692e1061ad7d5> or π(π₯,π)<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/3e3b8aafdf0be69fcd09cdb756b9c5aa2fd8c777> are used to indicate that π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/6e5ab2664b422d53eb0c7df3b87e1360d75ad9af> is regarded as a fixed unknown quantity rather than as a [https://en.wikipedia.org/wiki/Random_variable random variable] being conditioned on. The likelihood function does ''not'' specify the probability that π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/6e5ab2664b422d53eb0c7df3b87e1360d75ad9af> is the truth, given the observed sample π=π₯<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/0661396d873679039ffe8e908a39f02402d4912d>. Such an interpretation is a common error, with potentially disastrous consequences (see [https://en.wikipedia.org/wiki/Prosecutor's_fallacy prosecutor's fallacy]).<br/> <br/> full text link : [https://en.wikipedia.org/wiki/Likelihood_function https://en.wikipedia.org/wiki/Likelihood_function] === E-value === In [https://en.wikipedia.org/wiki/Statistical_hypothesis_testing statistical hypothesis testing], '''e-values''' quantify the evidence in the data against a [https://en.wikipedia.org/wiki/Null_hypothesis null hypothesis] (e.g., "the coin is fair", or, in a medical context, "this new treatment has no effect"). They serve as a more robust alternative to [https://en.wikipedia.org/wiki/P-value p-values], addressing some shortcomings of the latter. In contrast to p-values, e-values can deal with optional continuation: e-values of subsequent experiments (e.g. clinical trials concerning the same treatment) may simply be multiplied to provide a new, "product" e-value that represents the evidence in the joint experiment. This works even if, as often happens in practice, the decision to perform later experiments may depend in vague, unknown ways on the data observed in earlier experiments, and it is not known beforehand how many trials will be conducted: the product e-value remains a meaningful quantity, leading to tests with [https://en.wikipedia.org/wiki/Type_I_and_type_II_errors Type-I error control]. For this reason, e-values and their sequential extension, the ''e-process'', are the fundamental building blocks for anytime-valid statistical methods (e.g. confidence sequences). Another advantage over p-values is that any weighted average of e-values remains an e-value, even if the individual e-values are arbitrarily dependent. This is one of the reasons why e-values have also turned out to be useful tools in [https://en.wikipedia.org/wiki/Multiple_comparisons_problem multiple testing].<sup id="cite_ref-1">[https://en.wikipedia.org/wiki/E-values#cite_note-1 [1]]</sup> E-values can be interpreted in a number of different ways: first, the reciprocal of any e-value is itself a p-value, but a special, conservative one, quite different from p-values used in practice. Second, they are broad generalizations of [https://en.wikipedia.org/wiki/Likelihood_function likelihood ratios] and are also related to, yet distinct from, [https://en.wikipedia.org/wiki/Bayes_factors Bayes factors]. Third, they have an interpretation as bets. Finally, in a sequential context, they can also be interpreted as increments of nonnegative [https://en.wikipedia.org/wiki/Martingale_(probability_theory) supermartingales]. Interest in e-values has exploded since 2019, when the term 'e-value' was coined and a number of breakthrough results were achieved by several research groups. The first overview article appeared in 2023.<sup id="cite_ref-:2_2-0">[https://en.wikipedia.org/wiki/E-values#cite_note-:2-2 [2]]</sup><br/> <br/> Let the [https://en.wikipedia.org/wiki/Statistical_hypothesis_testing null hypothesis] π»0<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/43910602a221b7a4c373791f94793e3008622070> be given as a set of distributions for data π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/961d67d6b454b4df2301ac571808a3538b3a6d3f>. Usually π=(π1,β¦,ππ)<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/232436e83a6551876d9ea98a759d4e9681e80975> with each ππ<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/af4a0955af42beb5f85aa05fb8c07abedc13990d> a single outcome and π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/38a7dcde9730ef0853809fefc18d88771f95206c> a fixed sample size or some stopping time. We shall refer to such π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/961d67d6b454b4df2301ac571808a3538b3a6d3f>, which represent the full sequence of outcomes of a statistical experiment, as a ''sample'' or ''batch of outcomes.'' But in some cases π<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/961d67d6b454b4df2301ac571808a3538b3a6d3f> may also be an unordered bag of outcomes or a single outcome. An '''e-variable''' or '''e-statistic''' is a ''nonnegative'' random variable πΈ=πΈ(π)<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/2dff3e1e32d9281280efa425fc381f4348711c47> such that under all πβπ»0<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/975a55140fa8854be1a02c263d0dfdb74edff76a>, its expected value is bounded by 1: πΈπ[πΈ]β€1<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/1b5decf85768b772fff63e687c162ea50d8c3445>. The value taken by e-variable πΈ<img style="null" src=https://wikimedia.org/api/rest_v1/media/math/render/svg/4232c9de2ee3eec0a9c0a19b15ab92daa6223f9b> is called the '''e-value'''''.'' In practice, the term ''e-value'' (a number) is often used when one is really referring to the underlying e-variable (a random variable, that is, a measurable function of the data).<br/> <br/> full text link : [https://en.wikipedia.org/wiki/E-values https://en.wikipedia.org/wiki/E-values]<br/> == 2024.05.03 == === Tetrahymena === As a ciliated [https://en.wikipedia.org/wiki/Protozoan protozoan], '''''Tetrahymena thermophila''''' exhibits [https://en.wikipedia.org/wiki/Nuclear_dimorphism nuclear dimorphism]: two types of cell [https://en.wikipedia.org/wiki/Cell_nucleus nuclei]. They have a bigger, [https://en.wikipedia.org/wiki/Somatic_cell non-germline] [https://en.wikipedia.org/wiki/Macronucleus macronucleus] and a small, [https://en.wikipedia.org/wiki/Germline germline] [https://en.wikipedia.org/wiki/Micronucleus micronucleus] in each cell at the same time and these two carry out different functions with distinct cytological and biological properties. This unique versatility allows scientists to use ''Tetrahymena'' to identify several key factors regarding [https://en.wikipedia.org/wiki/Gene_expression gene expression] and genome integrity. In addition, ''Tetrahymena'' possess hundreds of [https://en.wikipedia.org/wiki/Cilia cilia] and has complicated [https://en.wikipedia.org/wiki/Microtubule microtubule] structures, making it an optimal model to illustrate the diversity and functions of microtubule arrays. Because ''Tetrahymena'' can be grown in a large quantity in the laboratory with ease, it has been a great source for biochemical analysis for years, specifically for [https://en.wikipedia.org/wiki/Enzyme enzymatic] activities and purification of [https://en.wikipedia.org/wiki/Cell_(biology)#Subcellular_components sub-cellular components]. In addition, with the advancement of genetic techniques it has become an excellent model to study the gene function ''in vivo''. The recent sequencing of the macronucleus genome should ensure that ''Tetrahymena'' will be continuously used as a model system. ''Tetrahymena thermophila'' exists in 7 different sexes ([https://en.wikipedia.org/wiki/Mating_type mating types]) that can reproduce in 21 different combinations, and a single tetrahymena cannot reproduce sexually with itself. Each organism "decides" which sex it will become during mating, through a [https://en.wikipedia.org/wiki/Stochastic stochastic] process.<sup id="cite_ref-PLOS2013_5-0">[https://en.wikipedia.org/wiki/Tetrahymena#cite_note-PLOS2013-5 [5]]</sup><sup id="cite_ref-6">[https://en.wikipedia.org/wiki/Tetrahymena#cite_note-6 [6]]</sup> Studies on ''Tetrahymena'' have contributed to several scientific milestones including: #First cell which showed synchronized division, which led to the first insights into the existence of mechanisms which control the [https://en.wikipedia.org/wiki/Cell_cycle cell cycle].<sup id="cite_ref-whitepaper_7-0">[https://en.wikipedia.org/wiki/Tetrahymena#cite_note-whitepaper-7 [7]]</sup> #Identification and purification of the first [https://en.wikipedia.org/wiki/Cytoskeleton cytoskeleton] based [https://en.wikipedia.org/wiki/Motor_protein motor protein] such as ''[https://en.wikipedia.org/wiki/Dynein dynein]''.<sup id="cite_ref-whitepaper_7-1">[https://en.wikipedia.org/wiki/Tetrahymena#cite_note-whitepaper-7 [7]]</sup> #Aid in the discovery of ''[https://en.wikipedia.org/wiki/Lysosomes lysosomes]'' and ''[https://en.wikipedia.org/wiki/Peroxisomes peroxisomes]''.<sup id="cite_ref-whitepaper_7-2">[https://en.wikipedia.org/wiki/Tetrahymena#cite_note-whitepaper-7 [7]]</sup> #Early molecular identification of somatic genome rearrangement.<sup id="cite_ref-whitepaper_7-3">[https://en.wikipedia.org/wiki/Tetrahymena#cite_note-whitepaper-7 [7]]</sup> #Discovery of the molecular structure of ''[https://en.wikipedia.org/wiki/Telomeres telomeres]'', ''[https://en.wikipedia.org/wiki/Telomerase telomerase]'' enzyme, the templating role of telomerase RNA and their roles in cellular senescence and chromosome healing (for which a Nobel Prize was won).<sup id="cite_ref-whitepaper_7-4">[https://en.wikipedia.org/wiki/Tetrahymena#cite_note-whitepaper-7 [7]]</sup> #Nobel Prizeβwinning co-discovery (1989, in Chemistry) of catalytic [https://en.wikipedia.org/wiki/RNA RNA] (''[https://en.wikipedia.org/wiki/Ribozymes ribozyme]'').<sup id="cite_ref-whitepaper_7-5">[https://en.wikipedia.org/wiki/Tetrahymena#cite_note-whitepaper-7 [7]]</sup><sup id="cite_ref-8">[https://en.wikipedia.org/wiki/Tetrahymena#cite_note-8 [8]]</sup> #Discovery of the function of [https://en.wikipedia.org/wiki/Histone histone] [https://en.wikipedia.org/wiki/Acetylation acetylation].<sup id="cite_ref-whitepaper_7-6">[https://en.wikipedia.org/wiki/Tetrahymena#cite_note-whitepaper-7 [7]]</sup> #Demonstration of the roles of [https://en.wikipedia.org/wiki/Posttranslational_modification posttranslational modification] such as acetylation and glycylation on [https://en.wikipedia.org/wiki/Tubulins tubulins] and discovery of the enzymes responsible for some of these modifications (glutamylation) #Crystal structure of 40S ribosome in complex with its initiation factor eIF1 #First demonstration that two of the "universal" [https://en.wikipedia.org/wiki/Stop_codon stop codons], UAA and UAG, will code for the amino acid [https://en.wikipedia.org/wiki/Glutamine glutamine] in some eukaryotes, leaving UGA as the only termination codon in these organisms.<sup id="cite_ref-9">[https://en.wikipedia.org/wiki/Tetrahymena#cite_note-9 [9]]</sup> <span style="font-size: 13.3333px;">link : [https://en.wikipedia.org/wiki/Tetrahymena https://en.wikipedia.org/wiki/Tetrahymena]</span><br/> === telomere === A '''telomere''' ([https://en.wikipedia.org/wiki/Help:IPA/English /ΛtΙlΙmΙͺΙr, ΛtiΛlΙ-/]; from [https://en.wikipedia.org/wiki/Ancient_Greek_language Ancient Greek] [https://en.wiktionary.org/wiki/ΟΞλοΟ#Ancient_Greek ΟΞλοΟ]'' (''tΓ©los'')'' 'end', and [https://en.wiktionary.org/wiki/ΞΌΞΟΞΏΟ#Ancient_Greek ΞΌΞΟΞΏΟ]'' (''mΓ©ros'')'' 'part') is a region of repetitive [https://en.wikipedia.org/wiki/Nucleotide nucleotide] sequences associated with specialized proteins at the ends of linear [https://en.wikipedia.org/wiki/Chromosome chromosomes] (see [https://en.wikipedia.org/wiki/Telomere#Sequences Sequences]). Telomeres are a widespread genetic feature most commonly found in [https://en.wikipedia.org/wiki/Eukaryote eukaryotes]. In most, if not all species possessing them, they protect the terminal regions of [https://en.wikipedia.org/wiki/DNA chromosomal DNA] from progressive degradation and ensure the integrity of linear chromosomes by preventing [https://en.wikipedia.org/wiki/DNA_repair DNA repair] systems from mistaking the very ends of the DNA strand for a [https://en.wikipedia.org/wiki/Double-strand_break double-strand break].<br/> The existence of a special structure at the ends of chromosomes was independently proposed in 1938 by [https://en.wikipedia.org/wiki/Hermann_Joseph_Muller Hermann Joseph Muller], studying the fruit fly ''[https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster]'', and in 1939 by [https://en.wikipedia.org/wiki/Barbara_McClintock Barbara McClintock], working with maize.<sup id="cite_ref-1">[https://en.wikipedia.org/wiki/Telomere#cite_note-1 [1]]</sup> Muller observed that the ends of irradiated fruit fly chromosomes did not present alterations such as deletions or inversions. He hypothesized the presence of a protective cap, which he coined "telomeres", from the Greek ''telos'' (end) and ''meros'' (part).<sup id="cite_ref-2">[https://en.wikipedia.org/wiki/Telomere#cite_note-2 [2]]</sup> In the early 1970s, Soviet theorist [https://en.wikipedia.org/wiki/Alexei_Olovnikov Alexei Olovnikov] first recognized that chromosomes could not completely replicate their ends; this is known as the "end replication problem". Building on this, and accommodating [https://en.wikipedia.org/wiki/Leonard_Hayflick Leonard Hayflick]'s idea of limited [https://en.wikipedia.org/wiki/Somatic_cell somatic cell] division, Olovnikov suggested that DNA sequences are lost every time a cell replicates until the loss reaches a critical level, at which point cell division ends.<sup id="cite_ref-3">[https://en.wikipedia.org/wiki/Telomere#cite_note-3 [3]]</sup><sup id="cite_ref-4">[https://en.wikipedia.org/wiki/Telomere#cite_note-4 [4]]</sup><sup id="cite_ref-5">[https://en.wikipedia.org/wiki/Telomere#cite_note-5 [5]]</sup> According to his theory of marginotomy DNA sequences at the ends of telomeres are represented by tandem repeats, which create a buffer that determines the number of divisions that a certain cell clone can undergo. Furthermore, it was predicted that a specialized DNA polymerase (originally called a tandem-DNA-polymerase) could extend telomeres in immortal tissues such as germ line, cancer cells and stem cells. It also followed from this hypothesis that organisms with circular genome, such as bacteria, do not have the end replication problem and therefore do not age. In 1975β1977, [https://en.wikipedia.org/wiki/Elizabeth_Blackburn Elizabeth Blackburn], working as a postdoctoral fellow at [https://en.wikipedia.org/wiki/Yale_University Yale University] with [https://en.wikipedia.org/wiki/Joseph_G._Gall Joseph G. Gall], discovered the unusual nature of telomeres, with their simple repeated DNA sequences composing chromosome ends.<sup id="cite_ref-:0_6-0">[https://en.wikipedia.org/wiki/Telomere#cite_note-:0-6 [6]]</sup> Blackburn, [https://en.wikipedia.org/wiki/Carol_Greider Carol Greider], and [https://en.wikipedia.org/wiki/Jack_Szostak Jack Szostak] were awarded the [https://en.wikipedia.org/wiki/List_of_Nobel_laureates_in_Physiology_or_Medicine#2001βcurrent 2009] [https://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicine Nobel Prize in Physiology or Medicine] for the discovery of how chromosomes are protected by telomeres and the [https://en.wikipedia.org/wiki/Enzyme enzyme] [https://en.wikipedia.org/wiki/Telomerase telomerase].<sup id="cite_ref-7">[https://en.wikipedia.org/wiki/Telomere#cite_note-7 [7]</sup><br/> <br/> During DNA replication, [https://en.wikipedia.org/wiki/DNA_polymerase DNA polymerase] cannot replicate the sequences present at the [https://en.wikipedia.org/wiki/Directionality_(molecular_biology) 3' ends] of the parent strands. This is a consequence of its unidirectional mode of DNA synthesis: it can only attach new nucleotides to an existing 3'-end (that is, synthesis progresses 5'-3') and thus it requires a [https://en.wikipedia.org/wiki/Primer_(molecular_biology) primer] to initiate replication. On the leading strand (oriented 5'-3' within the replication fork), DNA-polymerase continuously replicates from the point of initiation all the way to the strand's end with the primer (made of [https://en.wikipedia.org/wiki/RNA RNA]) then being excised and substituted by DNA. The lagging strand, however, is oriented 3'-5' with respect to the replication fork so continuous replication by DNA-polymerase is impossible, which necessitates discontinuous replication involving the repeated synthesis of primers further 5' of the site of initiation (see [https://en.wikipedia.org/wiki/Lagging_strand lagging strand replication]). The last primer to be involved in lagging-strand replication sits near the 3'-end of the template (corresponding to the potential 5'-end of the lagging-strand). Originally it was believed that the last primer would sit at the very end of the template, thus, once removed, the DNA-polymerase that substitutes primers with DNA (DNA-Pol Ξ΄ in eukaryotes)<sup id="cite_ref-note1_8-0">[https://en.wikipedia.org/wiki/Telomere#cite_note-note1-8 [note 1]]</sup> would be unable to synthesize the "replacement DNA" from the 5'-end of the lagging strand so that the template nucleotides previously paired to the last primer would not be replicated.<sup id="cite_ref-9">[https://en.wikipedia.org/wiki/Telomere#cite_note-9 [8]]</sup> It has since been questioned whether the last lagging strand primer is placed exactly at the 3'-end of the template and it was demonstrated that it is rather synthesized at a distance of about 70β100 nucleotides which is consistent with the finding that DNA in cultured human cell is shortened by 50β100 [https://en.wikipedia.org/wiki/Base_pair base pairs] per [https://en.wikipedia.org/wiki/Cell_division cell division].<sup id="cite_ref-10">[https://en.wikipedia.org/wiki/Telomere#cite_note-10 [9]]</sup> If coding sequences are degraded in this process, potentially vital genetic code would be lost. Telomeres are non-coding, repetitive sequences located at the termini of linear chromosomes to act as buffers for those coding sequences further behind. They "cap" the end-sequences and are progressively degraded in the process of DNA replication. The "end replication problem" is exclusive to linear chromosomes as circular chromosomes do not have ends lying without reach of DNA-polymerases. Most [https://en.wikipedia.org/wiki/Prokaryote prokaryotes], relying on circular chromosomes, accordingly do not possess telomeres.<sup id="cite_ref-11">[https://en.wikipedia.org/wiki/Telomere#cite_note-11 [10]]</sup> A small fraction of [https://en.wikipedia.org/wiki/Bacteria bacterial] chromosomes (such as those in ''[https://en.wikipedia.org/wiki/Streptomyces Streptomyces]'', ''[https://en.wikipedia.org/wiki/Agrobacterium Agrobacterium]'', and ''[https://en.wikipedia.org/wiki/Borrelia Borrelia]''), however, are linear and possess telomeres, which are very different from those of the eukaryotic chromosomes in structure and function. The known structures of bacterial telomeres take the form of [https://en.wikipedia.org/wiki/Proteins proteins] bound to the ends of linear chromosomes, or hairpin loops of single-stranded DNA at the ends of the linear chromosomes.<sup id="cite_ref-12">[https://en.wikipedia.org/wiki/Telomere#cite_note-12 [11]]</sup><br/> === Telomerase === '''Telomerase''', also called '''terminal transferase''',<sup id="cite_ref-1">[https://en.wikipedia.org/wiki/Telomerase#cite_note-1 [1]]</sup> is a [https://en.wikipedia.org/wiki/Ribonucleoprotein ribonucleoprotein] that adds a species-dependent [https://en.wikipedia.org/wiki/Telomere#Sequences telomere repeat sequence] to the [https://en.wikipedia.org/wiki/Directionality_(molecular_biology)#3.27-end 3'] end of [https://en.wikipedia.org/wiki/Telomere telomeres]. A telomere is a region of repetitive [https://en.wikipedia.org/wiki/Sequence_(biology) sequences] at each end of the [https://en.wikipedia.org/wiki/Chromosome chromosomes] of most [https://en.wikipedia.org/wiki/Eukaryote eukaryotes]. Telomeres protect the end of the chromosome from [https://en.wikipedia.org/wiki/DNA_damage_(naturally_occurring) DNA damage] or from fusion with neighbouring chromosomes. The fruit fly ''[https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster]'' lacks telomerase, but instead uses [https://en.wikipedia.org/wiki/Retrotransposon retrotransposons] to maintain telomeres.<sup id="cite_ref-pmid21821789_2-0">[https://en.wikipedia.org/wiki/Telomerase#cite_note-pmid21821789-2 [2]]</sup> Telomerase is a [https://en.wikipedia.org/wiki/Reverse_transcriptase reverse transcriptase] [https://en.wikipedia.org/wiki/Enzyme enzyme] that carries its own [https://en.wikipedia.org/wiki/Telomerase_RNA_component RNA molecule] (e.g., with the sequence 3β²-[https://en.wikipedia.org/wiki/Cytosine C]CC[https://en.wikipedia.org/wiki/Adenine A]A[https://en.wikipedia.org/wiki/Uracil U]CCC-5β² in ''[https://en.wikipedia.org/wiki/Trypanosoma_brucei Trypanosoma brucei]'')<sup id="cite_ref-pmid10097086_3-0">[https://en.wikipedia.org/wiki/Telomerase#cite_note-pmid10097086-3 [3]]</sup> which is used as a template when it elongates telomeres. Telomerase is active in [https://en.wikipedia.org/wiki/Gamete gametes] and most [https://en.wikipedia.org/wiki/Cancer cancer] cells, but is normally absent in most [https://en.wikipedia.org/wiki/Somatic_cell somatic cells].<br/> <br/> The existence of a compensatory mechanism for telomere shortening was first found by Soviet biologist [https://en.wikipedia.org/wiki/Alexey_Olovnikov Alexey Olovnikov] in 1973,<sup id="cite_ref-pmid4754905_4-0">[https://en.wikipedia.org/wiki/Telomerase#cite_note-pmid4754905-4 [4]]</sup> who also suggested the telomere hypothesis of [https://en.wikipedia.org/wiki/Aging aging] and the telomere's connections to cancer and perhaps some neurodegenerative diseases.<sup id="cite_ref-pmid16247010_5-0">[https://en.wikipedia.org/wiki/Telomerase#cite_note-pmid16247010-5 [5]]</sup> Telomerase in the ciliate ''[https://en.wikipedia.org/wiki/Tetrahymena Tetrahymena]'' was discovered by [https://en.wikipedia.org/wiki/Carol_W._Greider Carol W. Greider] and [https://en.wikipedia.org/wiki/Elizabeth_Blackburn Elizabeth Blackburn] in 1984.<sup id="cite_ref-pmid3907856_6-0">[https://en.wikipedia.org/wiki/Telomerase#cite_note-pmid3907856-6 [6]]</sup> Together with [https://en.wikipedia.org/wiki/Jack_W._Szostak Jack W. Szostak], Greider and Blackburn were awarded the 2009 [https://en.wikipedia.org/wiki/Nobel_Prize Nobel Prize] in [https://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicine Physiology or Medicine] for their discovery.<sup id="cite_ref-Nobel_Prize_2003_7-0">[https://en.wikipedia.org/wiki/Telomerase#cite_note-Nobel_Prize_2003-7 [7]]</sup> Later the [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy cryo-EM] structure of telomerase was first reported in ''T. thermophila'', to be followed a few years later by the cryo-EM structure of telomerase in humans.<sup id="cite_ref-pmid31451513_8-0">[https://en.wikipedia.org/wiki/Telomerase#cite_note-pmid31451513-8 [8]]</sup> The role of telomeres and telomerase in [https://en.wikipedia.org/wiki/Cellular_aging cell aging] and [https://en.wikipedia.org/wiki/Cancer cancer] was established by scientists at [https://en.wikipedia.org/wiki/Biotechnology biotechnology] company [https://en.wikipedia.org/wiki/Geron_Corporation Geron] with the cloning of the [https://en.wikipedia.org/wiki/RNA RNA] and catalytic components of human telomerase<sup id="cite_ref-9">[https://en.wikipedia.org/wiki/Telomerase#cite_note-9 [9]]</sup> and the development of a [https://en.wikipedia.org/wiki/Polymerase_chain_reaction polymerase chain reaction] (PCR) based assay for telomerase activity called the TRAP assay, which surveys telomerase activity in multiple types of cancer.<sup id="cite_ref-10">[https://en.wikipedia.org/wiki/Telomerase#cite_note-10 [10]]</sup> The [https://en.wikipedia.org/wiki/Negative_stain negative stain] electron microscopy (EM) structures of human and ''Tetrahymena'' telomerases were characterized in 2013.<sup id="cite_ref-11">[https://en.wikipedia.org/wiki/Telomerase#cite_note-11 [11]]</sup><sup id="cite_ref-12">[https://en.wikipedia.org/wiki/Telomerase#cite_note-12 [12]]</sup> Two years later, the first cryo-electron microscopy ([https://en.wikipedia.org/wiki/Cryo-EM cryo-EM]) structure of telomerase holoenzyme (''Tetrahymena'') was determined.<sup id="cite_ref-13">[https://en.wikipedia.org/wiki/Telomerase#cite_note-13 [13]]</sup> In 2018, the structure of human telomerase was determined through cryo-EM by UC Berkeley scientists.<sup id="cite_ref-14">[https://en.wikipedia.org/wiki/Telomerase#cite_note-14 [14]]</sup><br/> <br/> full text link : [https://en.wikipedia.org/wiki/Telomerase https://en.wikipedia.org/wiki/Telomerase] === DNA replicate === In [https://en.wikipedia.org/wiki/Molecular_biology molecular biology],<sup id="cite_ref-1">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-1 [1]]</sup><sup id="cite_ref-2">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-2 [2]]</sup><sup id="cite_ref-3">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-3 [3]]</sup> '''DNA replication''' is the [https://en.wikipedia.org/wiki/Biological_process biological process] of producing two identical replicas of DNA from one original [https://en.wikipedia.org/wiki/DNA DNA] molecule.<sup id="cite_ref-4">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-4 [4]]</sup> DNA replication occurs in all [https://en.wikipedia.org/wiki/Life living organisms] acting as the most essential part of [https://en.wikipedia.org/wiki/Heredity biological inheritance]. This is essential for cell division during growth and repair of damaged tissues, while it also ensures that each of the new cells receives its own copy of the DNA.<sup id="cite_ref-5">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-5 [5]]</sup> The cell possesses the distinctive property of division, which makes replication of DNA essential. DNA is made up of a [https://en.wikipedia.org/wiki/Nucleic_acid_double_helix double helix] of two [https://en.wikipedia.org/wiki/Complementary_DNA complementary] [https://en.wikipedia.org/wiki/DNA_strand strands]. The double helix describes the appearance of a double-stranded DNA which is thus composed of two linear strands that run opposite to each other and twist together to form.<sup id="cite_ref-6">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-6 [6]]</sup> During replication, these strands are separated. Each strand of the original DNA molecule then serves as a template for the production of its counterpart, a process referred to as [https://en.wikipedia.org/wiki/Semiconservative_replication semiconservative replication]. As a result of semi-conservative replication, the new helix will be composed of an original DNA strand as well as a newly synthesized strand.<sup id="cite_ref-7">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-7 [7]]</sup> Cellular [https://en.wikipedia.org/wiki/Proofreading_(Biology) proofreading] and error-checking mechanisms ensure near perfect [https://en.wikipedia.org/wiki/Fidelity fidelity] for DNA replication.<sup id="cite_ref-Berg_8-0">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-Berg-8 [8]]</sup><sup id="cite_ref-Alberts_9-0">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-Alberts-9 [9]]</sup> In a [https://en.wikipedia.org/wiki/Cell_(biology) cell], DNA replication begins at specific locations, or [https://en.wikipedia.org/wiki/Origin_of_replication origins of replication],<sup id="cite_ref-Hu_352.E2.80.93372_10-0">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-Hu_352β372-10 [10]]</sup> in the [https://en.wikipedia.org/wiki/Genome genome]<sup id="cite_ref-origins_11-0">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-origins-11 [11]]</sup> which contains the genetic material of an organism.<sup id="cite_ref-12">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-12 [12]]</sup> Unwinding of DNA at the origin and synthesis of new strands, accommodated by an [https://en.wikipedia.org/wiki/Enzyme enzyme] known as [https://en.wikipedia.org/wiki/Helicase helicase], results in [https://en.wikipedia.org/wiki/Replication_fork replication forks] growing bi-directionally from the origin. A number of [https://en.wikipedia.org/wiki/Protein proteins] are associated with the replication fork to help in the initiation and continuation of [https://en.wikipedia.org/wiki/DNA_synthesis DNA synthesis]. Most prominently, [https://en.wikipedia.org/wiki/DNA_polymerase DNA polymerase] synthesizes the new strands by adding [https://en.wikipedia.org/wiki/Nucleotide nucleotides] that complement each (template) strand. DNA replication occurs during the S-stage of [https://en.wikipedia.org/wiki/Interphase interphase].<sup id="cite_ref-13">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-13 [13]]</sup> DNA replication (DNA amplification) can also be performed ''[https://en.wikipedia.org/wiki/In_vitro in vitro]'' (artificially, outside a cell).<sup id="cite_ref-Jarillo-2021_14-0">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-Jarillo-2021-14 [14]]</sup> DNA polymerases isolated from cells and artificial DNA primers can be used to start DNA synthesis at known sequences in a template DNA molecule. [https://en.wikipedia.org/wiki/Polymerase_chain_reaction Polymerase chain reaction] (PCR), [https://en.wikipedia.org/wiki/Ligase_chain_reaction ligase chain reaction] (LCR), and [https://en.wikipedia.org/wiki/Transcription-mediated_amplification transcription-mediated amplification] (TMA) are examples. In March 2021, researchers reported evidence suggesting that a preliminary form of [https://en.wikipedia.org/wiki/Transfer_RNA transfer RNA], a necessary component of [https://en.wikipedia.org/wiki/Translation_(biology) translation], the biological synthesis of new [https://en.wikipedia.org/wiki/Protein proteins] in accordance with the [https://en.wikipedia.org/wiki/Genetic_code genetic code], could have been a replicator molecule itself in the very early development of life, or [https://en.wikipedia.org/wiki/Abiogenesis abiogenesis].<sup id="cite_ref-EL-20210302_15-0">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-EL-20210302-15 [15]]</sup><sup id="cite_ref-STD-20210403_16-0">[16]</sup><br/> ==== <sup id="cite_ref-STD-20210403_16-0">DNA Structure</sup> ==== DNA exists as a double-stranded structure, with both strands coiled together to form the characteristic [https://en.wikipedia.org/wiki/Double_helix double helix]. Each single strand of DNA is a chain of four types of [https://en.wikipedia.org/wiki/Nucleotide nucleotides]. Nucleotides in DNA contain a [https://en.wikipedia.org/wiki/Deoxyribose deoxyribose] sugar, a [https://en.wikipedia.org/wiki/Phosphate phosphate], and a [https://en.wikipedia.org/wiki/Nucleobase nucleobase]. The four types of [https://en.wikipedia.org/wiki/Nucleotide nucleotide] correspond to the four [https://en.wikipedia.org/wiki/Nucleobase nucleobases] [https://en.wikipedia.org/wiki/Adenine adenine], [https://en.wikipedia.org/wiki/Cytosine cytosine], [https://en.wikipedia.org/wiki/Guanine guanine], and [https://en.wikipedia.org/wiki/Thymine thymine], commonly abbreviated as A, C, G, and T. Adenine and guanine are [https://en.wikipedia.org/wiki/Purine pu]<sup id="cite_ref-17">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-17 [17]]</sup>[https://en.wikipedia.org/wiki/Purine rine] bases, while cytosine and thymine are [https://en.wikipedia.org/wiki/Pyrimidine pyrimidines]. These nucleotides form [https://en.wikipedia.org/wiki/Phosphodiester_bonds phosphodiester bonds], creating the phosphate-deoxyribose backbone of the DNA double helix with the nucleobases pointing inward (i.e., toward the opposing strand). Nucleobases are matched between strands through [https://en.wikipedia.org/wiki/Hydrogen_bonding hydrogen bonds] to form [https://en.wikipedia.org/wiki/Base_pair base pairs]. Adenine pairs with thymine (two hydrogen bonds), and guanine pairs with cytosine (three [https://en.wikipedia.org/wiki/Hydrogen_bonds hydrogen bonds]).<sup id="cite_ref-18">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-18 [18]]</sup> [https://en.wikipedia.org/wiki/Directionality_(molecular_biology) DNA strands have a directionality], and the different ends of a single strand are called the "3β² (three-prime) end" and the "5β² (five-prime) end". By convention, if the base sequence of a single strand of DNA is given, the left end of the sequence is the 5β² end, while the right end of the sequence is the 3β² end. The strands of the double helix are anti-parallel, with one being 5β² to 3β², and the opposite strand 3β² to 5β². These terms refer to the carbon atom in deoxyribose to which the next phosphate in the chain attaches. Directionality has consequences in DNA synthesis, because DNA polymerase can synthesize DNA in only one direction by adding nucleotides to the 3β² end of a DNA strand. The pairing of complementary bases in DNA (through [https://en.wikipedia.org/wiki/Hydrogen_bonding hydrogen bonding]) means that the information contained within each strand is redundant. Phosphodiester (intra-strand) bonds are stronger than hydrogen (inter-strand) bonds. The actual job of the phosphodiester bonds is where in DNA polymers connect the 5' carbon atom of one nucleotide to the 3' carbon atom of another nucleotide, while the hydrogen bonds stabilize DNA double helices across the helix axis but not in the direction of the axis.<sup id="cite_ref-19">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-19 [19]]</sup> This makes it possible to separate the strands from one another. The nucleotides on a single strand can therefore be used to reconstruct nucleotides on a newly synthesized partner strand.<sup id="cite_ref-20">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-20 [20]]</sup><br/> ==== <sup id="cite_ref-20">DNA polymerase</sup> ==== [https://en.wikipedia.org/wiki/DNA_polymerase DNA polymerases] are a family of [https://en.wikipedia.org/wiki/Enzyme enzymes] that carry out all forms of DNA replication.<sup id="cite_ref-22">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-22 [22]]</sup> DNA polymerases in general cannot initiate synthesis of new strands but can only extend an existing DNA or RNA strand paired with a template strand. To begin synthesis, a short fragment of RNA, called a [https://en.wikipedia.org/wiki/Primer_(molecular_biology) primer], must be created and paired with the template DNA strand. DNA polymerase adds a new strand of DNA by extending the 3β² end of an existing nucleotide chain, adding new [https://en.wikipedia.org/wiki/Nucleotide nucleotides] matched to the template strand, one at a time, via the creation of [https://en.wikipedia.org/wiki/Phosphodiester_bond phosphodiester bonds]. The energy for this process of DNA polymerization comes from hydrolysis of the [https://en.wikipedia.org/wiki/High-energy_phosphate high-energy phosphate] (phosphoanhydride) bonds between the three phosphates attached to each unincorporated [https://en.wikipedia.org/wiki/Nucleotide base]. Free bases with their attached phosphate groups are called [https://en.wikipedia.org/wiki/Nucleotide nucleotides]; in particular, bases with three attached phosphate groups are called [https://en.wikipedia.org/wiki/Nucleoside_triphosphate nucleoside triphosphates]. When a nucleotide is being added to a growing DNA strand, the formation of a phosphodiester bond between the proximal phosphate of the nucleotide to the growing chain is accompanied by hydrolysis of a high-energy phosphate bond with release of the two distal phosphate groups as a [https://en.wikipedia.org/wiki/Pyrophosphate pyrophosphate]. Enzymatic hydrolysis of the resulting [https://en.wikipedia.org/wiki/Pyrophosphate pyrophosphate] into inorganic phosphate consumes a second high-energy phosphate bond and renders the reaction effectively irreversible.<sup id="cite_ref-23">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-23 [Note 1]]</sup> In general, DNA polymerases are highly accurate, with an intrinsic error rate of less than one mistake for every 10<sup>7</sup> nucleotides added.<sup id="cite_ref-pmid18166979_24-0">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-pmid18166979-24 [23]]</sup> Some DNA polymerases can also delete nucleotides from the end of a developing strand in order to fix mismatched bases. This is known as proofreading. Finally, post-replication mismatch repair mechanisms monitor the DNA for errors, being capable of distinguishing mismatches in the newly synthesized DNA Strand from the original strand sequence. Together, these three discrimination steps enable replication fidelity of less than one mistake for every 10<sup>9</sup> nucleotides added.<sup id="cite_ref-pmid18166979_24-1">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-pmid18166979-24 [23]]</sup> The rate of DNA replication in a living cell was first measured as the rate of phage T4 DNA elongation in phage-infected ''E. coli''.<sup id="cite_ref-25">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-25 [24]]</sup> During the period of exponential DNA increase at 37 Β°C, the rate was 749 nucleotides per second. The mutation rate per base pair per replication during phage T4 DNA synthesis is 1.7 per 10<sup>8</sup>.<sup id="cite_ref-26">[https://en.wikipedia.org/wiki/DNA_replication#cite_note-26 [25]]</sup><br/> === Transposase === a cut-and-paste mechanism or a replicative mechanism, in a process known as transposition. The word "transposase" was first coined by the individuals who cloned the enzyme required for transposition of the [https://en.wikipedia.org/wiki/Tn3_Transposon Tn3 transposon].<sup id="cite_ref-1">[https://en.wikipedia.org/wiki/Transposase#cite_note-1 [1]]</sup> The existence of transposons was postulated in the late 1940s by [https://en.wikipedia.org/wiki/Barbara_McClintock Barbara McClintock], who was studying the inheritance of [https://en.wikipedia.org/wiki/Maize maize], but the actual molecular basis for transposition was described by later groups. McClintock discovered that some segments of [https://en.wikipedia.org/wiki/Chromosome chromosomes] changed their position, jumping between different loci or from one chromosome to another. The repositioning of these transposons (which coded for color) allowed other genes for pigment to be expressed.<sup id="cite_ref-website1_2-0">[https://en.wikipedia.org/wiki/Transposase#cite_note-website1-2 [2]]</sup> Transposition in maize causes changes in color; however, in other organisms, such as bacteria, it can cause [https://en.wikipedia.org/wiki/Antimicrobial_resistance antibiotic resistance].<sup id="cite_ref-website1_2-1">[https://en.wikipedia.org/wiki/Transposase#cite_note-website1-2 [2]]</sup> Transposition is also important in creating genetic diversity within species and generating adaptability to changing living conditions.<sup id="cite_ref-MM_3-0">[https://en.wikipedia.org/wiki/Transposase#cite_note-MM-3 [3]]</sup> Transposases are classified under [https://en.wikipedia.org/wiki/Enzyme_Commission_number EC number] EC 2.7.7. Genes encoding transposases are widespread in the genomes of most organisms and are the most abundant genes known.<sup id="cite_ref-4">[https://en.wikipedia.org/wiki/Transposase#cite_note-4 [4]]</sup> During the course of human evolution, as much as 40% of the human genome has moved around via methods such as transposition of transposons.<sup id="cite_ref-website1_2-2">[https://en.wikipedia.org/wiki/Transposase#cite_note-website1-2 [2]]</sup><br/> ==== Transposase Tn5 ==== Transposase (Tnp) Tn5 is a member of the [https://en.wikipedia.org/wiki/Ribonuclease RNase] superfamily of proteins which includes retroviral [https://en.wikipedia.org/wiki/Integrase integrases]. Tn5 can be found in ''[https://en.wikipedia.org/wiki/Shewanella Shewanella]'' and ''[https://en.wikipedia.org/wiki/Escherichia Escherichia]'' bacteria.<sup id="cite_ref-Website2_5-0">[https://en.wikipedia.org/wiki/Transposase#cite_note-Website2-5 [5]]</sup> The transposon codes for antibiotic resistance to [https://en.wikipedia.org/wiki/Kanamycin kanamycin] and other aminoglycoside antibiotics.<sup id="cite_ref-MM_3-1">[https://en.wikipedia.org/wiki/Transposase#cite_note-MM-3 [3]]</sup><sup id="cite_ref-N1_6-0">[https://en.wikipedia.org/wiki/Transposase#cite_note-N1-6 [6]]</sup> Tn5 and other transposases are notably inactive. Because DNA transposition events are inherently mutagenic, the low activity of transposases is necessary to reduce the risk of causing a fatal mutation in the host, and thus eliminating the [https://en.wikipedia.org/wiki/Transposable_element transposable element]. One of the reasons Tn5 is so unreactive is because the N- and C-termini are located in relatively close proximity to one another and tend to inhibit each other. This was elucidated by the characterization of several mutations which resulted in hyperactive forms of transposases. One such mutation, L372P, is a mutation of amino acid 372 in the Tn5 transposase. This amino acid is generally a leucine residue in the middle of an alpha helix. When this leucine is replaced with a proline residue the alpha helix is broken, introducing a conformational change to the C-terminal domain, separating it from the N-terminal domain enough to promote higher activity of the protein.<sup id="cite_ref-MM_3-2">[https://en.wikipedia.org/wiki/Transposase#cite_note-MM-3 [3]]</sup> The transposition of a transposon often needs only three pieces: the transposon, the transposase enzyme, and the target DNA for the insertion of the transposon.<sup id="cite_ref-MM_3-3">[https://en.wikipedia.org/wiki/Transposase#cite_note-MM-3 [3]]</sup> This is the case with Tn5, which uses a cut-and-paste mechanism for moving around transposons.<sup id="cite_ref-MM_3-4">[https://en.wikipedia.org/wiki/Transposase#cite_note-MM-3 [3]]</sup> Tn5 and most other transposases contain a DDE motif, which is the active site that catalyzes the movement of the transposon. Aspartate-97, aspartate-188, and glutamate-326 make up the active site, which is a triad of acidic residues.<sup id="cite_ref-BC_7-0">[https://en.wikipedia.org/wiki/Transposase#cite_note-BC-7 [7]]</sup> The DDE motif is said to coordinate divalent metal ions, most often magnesium and manganese, which are important in the catalytic reaction.<sup id="cite_ref-BC_7-1">[https://en.wikipedia.org/wiki/Transposase#cite_note-BC-7 [7]]</sup> Because transposase is incredibly inactive, the DDE region is mutated so that the transposase becomes hyperactive and catalyzes the movement of the transposon.<sup id="cite_ref-BC_7-2">[https://en.wikipedia.org/wiki/Transposase#cite_note-BC-7 [7]]</sup> The glutamate is transformed into an aspartate and the two aspartates into glutamates.<sup id="cite_ref-BC_7-3">[https://en.wikipedia.org/wiki/Transposase#cite_note-BC-7 [7]]</sup> Through this mutation, the study of Tn5 becomes possible, but some steps in the catalytic process are lost as a result.<sup id="cite_ref-MM_3-5">[https://en.wikipedia.org/wiki/Transposase#cite_note-MM-3 [3]]</sup> <br/> <br/> <br/> <br/> [https://biolecture.org/Main_Page Main Page] Β» [https://biolecture.org/UNIST_Geromics_course UNIST Geromics course] Β» [https://biolecture.org/Geromics_Course_Students_Folder_2024 Geromics Course Students Folder 2024] Β» [https://biolecture.org/HyoungJinChoi_2024_Geromics_Course HyoungJinChoi 2024 Geromics Course] Β» [https://biolecture.org/Summary_class_Geromics_2024_HyoungJinChoi Summary class Geromics 2024 HyoungJinCho]