The X-inactive specific transcript ( Xist ) gene encodes a large  non-coding RNA  that is responsible for mediating the specific silencing of the X chromosome from which it is transcribed. [ 30 ]  The inactive X chromosome is coated by Xist RNA, [ 31 ]  whereas the Xa is not (See Figure to the right). X chromosomes that lack the Xist gene cannot be inactivated. [ 32 ]  Artificially placing and expressing the Xist gene on another chromosome leads to silencing of that chromosome. [ 33 ] [ 27 ]


Prior to inactivation, both X chromosomes weakly express Xist RNA from the Xist gene. During the inactivation process, the future Xa ceases to express Xist, whereas the future Xi dramatically increases Xist RNA production. On the future Xi, the Xist RNA progressively coats the chromosome, spreading out from the XIC; [ 33 ]  the Xist RNA does not localize to the Xa. The  silencing of genes  along the Xi occurs soon after coating by Xist RNA.


Like Xist, the  Tsix  gene encodes a large RNA which is not believed to encode a protein. The Tsix RNA is transcribed  antisense  to Xist, meaning that the Tsix gene overlaps the Xist gene and is  transcribed  on the opposite strand of  DNA  from the Xist gene. [ 28 ]  Tsix is a negative regulator of Xist; X chromosomes lacking Tsix expression (and thus having high levels of Xist transcription) are inactivated much more frequently than normal chromosomes.


Like Xist, prior to inactivation, both X chromosomes weakly express Tsix RNA from the Tsix gene. Upon the onset of X-inactivation, the future Xi ceases to express Tsix RNA (and increases Xist expression), whereas Xa continues to express Tsix for several days.


Rep A is a long non coding RNA that works with another long non coding RNA, Xist, for X inactivation. Rep A inhibits the function of Tsix, the antisense of Xist, in conjunction with eliminating expression of Xite. It promotes methylation of the Tsix region by attracting PRC2 and thus inactivating one of the X chromosomes. [ 29 ]


The inactive X chromosome does not express the majority of its genes, unlike the active X chromosome. This is due to the silencing of the Xi by repressive  heterochromatin , which compacts the Xi DNA and prevents the expression of most genes.


Compared to the Xa, the Xi has high levels of  DNA methylation , low levels of  histone acetylation , low levels of  histone H3  lysine-4  methylation , and high levels of histone H3 lysine-9 methylation and H3 lysine-27 methylation mark which is placed by the  PRC2 complex recruited by Xist , all of which are associated with gene silencing. [ 34 ]   PRC2  regulates  chromatin  compaction and  chromatin remodeling  in several processes including the  DNA damage  response. [ 35 ]  Additionally, a histone variant called macroH2A ( H2AFY ) is exclusively found on  nucleosomes  along the Xi. [ 36 ] [ 37 ]


DNA packaged in heterochromatin, such as the Xi, is more condensed than DNA packaged in  euchromatin , such as the Xa. The inactive X forms a discrete body within the nucleus called a  Barr body . [ 38 ]  The Barr body is generally located on the periphery of the  nucleus , is late  replicating  within the  cell cycle , and, as it contains the Xi, contains heterochromatin modifications and the Xist RNA.


A fraction of the genes along the X chromosome escape inactivation on the Xi. The Xist gene is expressed at high levels on the Xi and is not expressed on the Xa. [ 39 ]  Many other genes escape inactivation; some are expressed equally from the Xa and Xi, and others, while expressed from both chromosomes, are still predominantly expressed from the Xa. [ 40 ] [ 41 ] [ 42 ]  Up to one quarter of genes on the human Xi are capable of escape. [ 40 ]  Studies in the mouse suggest that in any given cell type, 3% to 15% of genes escape inactivation, and that escaping gene identity varies between tissues. [ 41 ] [ 42 ]


Many of the genes which escape inactivation are present along regions of the X chromosome which, unlike the majority of the X chromosome, contain genes also present on the  Y chromosome . These regions are termed  pseudoautosomal  regions, as individuals of either sex will receive two copies of every gene in these regions (like an autosome), unlike the majority of genes along the sex chromosomes. Since individuals of either sex will receive two copies of every gene in a  pseudoautosomal region , no dosage compensation is needed for females, so it is postulated that these regions of DNA have evolved mechanisms to escape X-inactivation. The genes of pseudoautosomal regions of the Xi do not have the typical modifications of the Xi and have little Xist RNA bound.


The existence of genes along the inactive X which are not silenced explains the defects in humans with atypical numbers of the X chromosome, such as  Turner syndrome  (X0, caused by SHOX gene [ 43 ] ) or  Klinefelter syndrome  (XXY). Theoretically, X-inactivation should eliminate the differences in gene dosage between affected individuals and individuals with a typical chromosome complement. In affected individuals, however, X-inactivation is incomplete and the dosage of these non-silenced genes will differ as they escape X-inactivation, similar to an autosomal  aneuploidy .


The precise mechanisms that control escape from X-inactivation are not known, but silenced and escape regions have been shown to have distinct chromatin marks. [ 41 ] [ 44 ]  It has been suggested that escape from X-inactivation might be mediated by expression of  long non-coding RNA  (lncRNA) within the escaping chromosomal domains. [ 2 ]


Stanley Michael Gartler  used X-chromosome inactivation to demonstrate the clonal origin of cancers. Examining normal tissues and tumors from females heterozygous for isoenzymes of the sex-linked  G6PD  gene demonstrated that tumor cells from such individuals express only one form of G6PD, whereas normal tissues are composed of a nearly equal mixture of cells expressing the two different phenotypes. This pattern suggests that a single cell, and not a population, grows into a cancer. [ 45 ]  However, this pattern has been proven wrong for many cancer types, suggesting that some cancers may be polyclonal in origin. [ 46 ]


Besides, measuring the methylation (inactivation) status of the polymorphic human androgen receptor (HUMARA) located on X-chromosome is considered the most accurate method to assess clonality in female cancer biopsies. [ 47 ]  A great variety of tumors was tested by this method, some, such as renal cell carcinoma, [ 48 ]  found monoclonal while others (e.g. mesothelioma [ 49 ] ) were reported polyclonal.


Researchers have also investigated using X-chromosome inactivation to silence the activity of autosomal chromosomes. For example, Jiang  et al.  inserted a copy of the Xist gene into one copy of chromosome 21 in  stem cells  derived from an individual with trisomy 21 ( Down syndrome ). [ 50 ]  The inserted Xist gene induces Barr body formation, triggers stable heterochromatin modifications, and silences most of the genes on the extra copy of chromosome 21. In these modified stem cells, the Xist-mediated gene silencing seems to reverse some of the defects associated with Down syndrome.


In 1959  Susumu Ohno  showed that the two X chromosomes of mammals were different: one appeared similar to the  autosomes ; the other was condensed and heterochromatic. [ 51 ]  This finding suggested, independently to two groups of investigators, that one of the X chromosomes underwent inactivation.


In 1961,  Mary Lyon  proposed the random inactivation of one female X chromosome to explain the mottled phenotype of female mice  heterozygous  for coat color  genes . [ 52 ]  The Lyon hypothesis also accounted for the findings that one copy of the X chromosome in female cells was highly condensed, and that mice with only one copy of the X chromosome developed as infertile females. This suggested [ 53 ]  to  Ernest Beutler , studying heterozygous females for  glucose-6-phosphate dehydrogenase  (G6PD) deficiency, that there were two red cell populations of erythrocytes in such heterozygotes: deficient cells and normal cells, [ 54 ]  depending on whether the inactivated X chromosome (in the nucleus of the red cell's precursor cell) contains the normal or defective G6PD allele.


Biological dark matter  is an informal term for unclassified or poorly understood  genetic material . This genetic material may refer to genetic material produced by unclassified  microorganisms . By extension, biological dark matter may also refer to the un-isolated microorganisms whose existence can only be inferred from the genetic material that they produce. Some of the genetic material may not fall under the three existing domains of life:  Bacteria ,  Archaea  and  Eukaryota ; thus, it has been suggested that a possible fourth domain of life may yet be discovered, [ 1 ] [ 2 ]  although other explanations are also probable. Alternatively, the genetic material may refer to  non-coding DNA  (so-called "junk DNA") [ 3 ] [ 4 ] [ 5 ]  and  non-coding RNA  produced by known organisms. [ 6 ] [ 7 ] [ 8 ]


Much of the genomic dark matter is thought to originate from ancient  transposable elements  and from other low-complexity repetitive elements. [ 9 ] [ 10 ]  Uncategorized  genetic material  is found in  humans  and many other species. [ 1 ] [ 11 ]  Their  phylogenetic  novelty could indicate the cellular  organisms  or  viruses  from which they evolved. [ 12 ]


Up to 99% of all living  microorganisms  cannot be  cultured , [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ]  so few functional insights exist about the  metabolic potential  of these organisms.


Sequences that are believed to be derived from unknown microbes are referred to as the microbial dark matter, [ 18 ]  the dark  virome , [ 19 ]  or dark matter fungi. [ 20 ]  Such sequences are not rare. It has been estimated that in material from humans, between 40 and 90% of viral sequences are from dark matter. [ 21 ] [ 22 ] [ 23 ]  Human blood contains over three thousand different DNA sequences which cannot yet be identified. [ 24 ]  A mycological study from 2023 found that dark matter fungi seem to dominate the fungal kingdom.  [ 25 ]


Algorithms have been developed that examine sequences for similarities to bacterial  16S RNA  sequences, [ 26 ]   K-mer  similarities to known viruses, [ 27 ]  specific features of  codon  usage, [ 28 ]  or for inferring the existence of proteins. [ 29 ]  These approaches have suggested, for example, the existence of a novel  bacteriophage  of the  microviridae  family, [ 29 ]  and a novel bacterioidales-like phage. [ 30 ]  Other studies have suggested the existence of 264 new viral genera, discovered in publicly available databases, [ 31 ]  and a study of human blood suggested that 42% of people have at least one previously unknown virus each, adding up to 19 different new genera. [ 32 ]  A comprehensive study of DNA sequences from multiple human samples inferred the existence of 4,930 species of microbes of which 77% were previously unreported. [ 33 ]  Health-related findings include a  prophage  that might be associated with  cirrhosis of the liver , [ 27 ]  and seven novel sequences from children with  type-1 diabetes  that have characteristics of viruses. [ 34 ]  Although they might exist, no organisms that clearly cause human disease have been discovered in the dark matter.


In February 2023, scientists reported the findings of unusual DNA strands from the microorganisms in the "dark microbiome" in the  driest non-polar desert  on Earth. [ 35 ] [ 36 ]


Cis-action  or  cis-acting  is a vague term that, in general, means "an action on the same" in contrast to  trans-action  "an action on a different". In other words, the initiator of the action is affected by it. Cis-actions occur wherever  circular dependencies  are present. Most notably in:


In  philology  and  linguistics ,  decipherment  is the discovery of the meaning of the symbols found in extinct  languages  and/or  alphabets . [ 1 ]  Decipherment is possible with respect to languages and scripts. One can also study or try to decipher how spoken languages that no longer exist were once pronounced, or how living languages used to be pronounced in prior eras.


Notable examples of decipherment include the  decipherment of ancient Egyptian scripts  and the  decipherment of cuneiform . A notable decipherment in recent years is that of the  Linear Elamite  script. [ 2 ]  Today, at least a dozen languages remain undeciphered. [ 3 ]  Historically speaking, decipherments do not come suddenly through single individuals who "crack" ancient scripts. Instead, they emerge from the incremental progress brought about by a broader community of researchers. [ 4 ]


Decipherment should not be confused with  cryptanalysis , which aims to decipher special written codes or  cipher s used in intentionally concealed secret communication (especially during war). It should also not be confused with determining the meaning of ambiguous text in a known language (interpretation). [ 4 ]


According to Gelb and Whiting, the approach of decipherment depends on four categories of situations in an undeciphered language: [ 5 ] [ 6 ]


There is no single recipe or linear method for decipherment, however: instead, philologists and linguists must rely on a set of  heuristic devices  that have been established. Broadly, it is important to be familiar with the relevant texts where the script or language occurs in, access to accurate drawings or photographs of these texts, information about their relative chronology, and background information on where the texts occur in (their geography, perhaps being found in the context of a funerary monument, etc). [ 4 ]


These methods can be divided into approaches utilizing external or internal information. [ 5 ]


Many successful encipherments have proceeded from the discovery of external information, a common example being through the use of  multilingual inscriptions , such as the  Rosetta Stone  (with the same text in three scripts:  Demotic ,  hieroglyphic , and  Greek ) that enabled the decipherment of Egyptian hieroglyphic. In principle, multilingual text may be insufficient for a decipherment as translation is not a linear and reversible process, but instead represents an encoding of the message in a different symbolic system. Translating a text from one language into a second, and then from the second language back into the first, rarely reproduces exactly the original writing. Likewise, unless a significant number of words are contained in the multilingual text, limited information can be gleaned from it. [ 5 ]


Internal approaches are multi-step: one must first ensure that the writing they are looking at represents real writing, as opposed to a grouping of pictorial representations or a modern-day forgery without further meaning. This is commonly approached with methods from the field of  grammatology . Prior to decipherment of meaning, one can then determine the number of distinct  graphemes  (which, in turn, allows one to tell if the writing system is alphabetic, syllabic, or logo-syllabic; this is because such writing systems typically do not overlap in the number of graphemes they use [ 6 ] ), the sequence of writing (whether it be from left to right, right to left, top to bottom, etc.), and the determination of whether individual words are properly segmented when the alphabet is written (such as with the use of a space or a different special mark) or not. If a repetitive schematic arrangement can be identified, this can help in decipherment. For example, if the last line of a text has a small number, it can be reasonably guessed to be referring to the date, where one of the words means "year" and, sometimes, a royal name also appears. Another case is when the text contains many small numbers, followed by a word, followed by a larger number; here, the word likely means "total" or "sum". After one has exhausted the information that can be inferentially derived from probable content, they must transition to the systematic application of statistical tools. These include methods concerning the frequency of appearance of each symbol, the order in which these symbols typically appear, whether some symbols appear at the beginning or end of words, etc. There are situations where orthographic features of a language make it difficult if not impossible to decipher specific features (especially without certain outside information), such as when an alphabet does not express double consonants. Additional, and more complex methods, also exist. Eventually, the application of such statistical methods becomes exceedingly laborious, in which computers might be used to apply them automatically. [ 5 ]


Computational approaches towards the decipherment of unknown languages began to appear in the late 1990s. [ 7 ]  Typically, there are two types of computational approaches used in language decipherment: approaches meant to produce translations in known languages, and approaches used to detect new information that might enable future efforts at translation. The second approach is more common, and includes things such as the detection of cognates or related words, discovery of the closest known language, word alignments, and more. [ 6 ]


In recent years, there has been a growing emphasis on methods utilizing  artificial intelligence  for the decipherment of lost languages, especially through  natural language processing  (NLP) methods. Proof-of-concept methods have independently re-deciphered  Ugaritic  and  Linear B  using data from similar languages, in this case  Hebrew  and  Ancient Greek . [ 8 ]


Related to attempts to decipher the meaning of languages and alphabets, include attempts to decipher how extinct writing systems, or older versions of contemporary writing systems (such as English in the 1600s) were pronounced. Several methods and criteria have been developed in this regard. Important criteria include (1) Rhymes and the testimony of poetry (2) Evidence from occasional spellings and misspellings (3) Interpretations of material in one language from authors in foreign languags (4) Information obtained from related languages (5) Grammatical changes in spelling over time. [ 9 ]


For example, analysis of poetry focuses on the use of wordplay or literary techniques between words that have a similar sound.  Shakespeare 's play  Romeo and Juliet  contains wordplay that relies on a similar sound between the words "soul" and "soles", allowing confidence that the similar pronunciation between the terms today also existed in Shakespeare's time. Another common source of information on pronunciation is when earlier texts use  rhyme , such as when consecutive lines in poetry end in the similar or the same sound. This method does have some limitations however, as texts may use rhymes that rely on visual similarities between words (such as 'love' and 'remove') as opposed to auditory similarities, and that rhymes can be  imperfect . Another source of information about pronunciation comes from explicit description of pronunciations from earlier texts, as in the case of the  Grammatica Anglicana , such as in the following comment about the letter <o>: "In the long time it naturally soundeth sharp, and high; as in chósen, hósen, hóly, fólly [. . .] In the short time more flat, and a kin to u; as còsen, dòsen, mòther, bròther, lòve, pròve". [ 10 ]  Another example comes from detailed comments on pronunciations of  Sanskrit  from the surviving works of Sanskrit grammarians. [ 9 ]


Many challenges exist in the decipherment of languages, including when: [ 3 ] [ 6 ]


Decipherment overlaps with another technical field known as  cryptanalysis , a field that aims to decipher writings used in secret communication, known as  ciphertext . A famous case of this was in the  cryptanalysis of the Enigma  during the  World War II . Many other ciphers from past wars have only recently been cracked. [ 11 ]  Unlike in language decipherment, however, actors using ciphertext intentionally lay obstacles to prevent outsiders from uncovering the meaning of the communication system. [ 5 ]


Interest in ancient scripts and dead languages began to arise by the  Renaissance , if not earlier. Extensive information began to be collected about these scripts in the 16th and 17th centuries, and a typology of writing was established in the 17th century. The first serious decipherments, however, did not take place until the 18th century. In 1754, Swinton and Barthélemy independently deciphered the Aramaic script as represented in Palmyrene inscriptions from the 3rd century AD. In 1787,  Silvestre de Sacy  deciphered the  Sasanian script , which was the script used in  Ancient Persia  to write down the  Middle Iranian  language used in the  Sasanian empire . Both decipherments relied on bilingual texts where Greek was included as the second script. It was also in the 18th century when the methodological framework for deciphering scripts and languages began to be established. For example, in 1714,  Leibniz  advocated that parallel content in bilingual inscriptions could be specified by correlating where personal names occur in both inscriptions. By the 19th century, the prerequisites for decipherment began to become widely available. These included extensive knowledge about the scripts themselves, adequate editions of known texts from that script, philological skills, and the ability to reconstruct linguistic forms from the limited available evidence. The 19th century saw two major successes in decipherment: that of  Egyptian hieroglyphic  and  cuneiform . [ 4 ]


Gene-environment interplay  describes how  genes  and  environments  work together to produce a  phenotype , or observable trait.  Many human traits are influenced by gene-environment interplay. It is a key component in understanding how genes and the environment come together to impact  human development . Examples of gene-environment interplay include  gene-environment interaction  and  gene-environment correlation . [ 1 ]   Another type of gene-environment interplay is  epigenetics , which is the study of how environmental factors can affect  gene expression  without altering DNA sequences. [ 2 ]


To study the effect of the environment on the expression of the human genome, family-based  behavioral genetic  research methods such as  twin ,  family  and  adoption studies  are used. [ 1 ]  Moreover, the identification of genes under environmental influence can be completed through  genome-wide association studies. [ 3 ]  Research on cases of gene-environment interplay allow for a deeper understanding of the nuances surrounding  nature versus nurture  debates. Environmental factors can cause deviations from expected gene expression, which ultimately impact cellular processes, such as  cell signaling . They can also affect the likelihood of  disease . By identifying environmental effects on cellular processes, scientists can gain a better understanding of the mechanisms behind diseases and gain insights into treating them. [ 4 ]


Gene–environment interaction  occurs when genetic factors and environmental factors interact to produce an outcome that cannot be explained by either factor alone. [ 6 ]  For example, a study found that individuals carrying the genetic variant  5-HTT  (the short copy) that encodes the  serotonin  transporter were at a higher risk of developing  depression  when exposed to adverse childhood experiences, whereas those with other genotypes (long copy) were less affected by  childhood maltreatment . However, there is a caveat as these stressful events may also be caused by an individual's predisposition for getting into these situations. [ 7 ]


Gene–environment correlations  describe how different environmental exposures are statistically linked to genes. [ 8 ]  These correlations can emerge through multiple different mechanisms, both causal and non-causal. [ 9 ]  In regard to  causal mechanisms , there are three common types of gene-environment correlations: [ 9 ]


The childhood environment of an individual may be correlated with their inherited genes, since an individual's parents may have selected for their childhood environment. [ 5 ]  This type of correlation is considered "passive" since the child's environment is being determined by parental decisions rather than by the child's own decisions. For example, parents who have high  openness-to-experience , which is a moderately  heritable  personality trait, are more likely to provide their children with  musical training . [ 10 ]  Consequently, a correlation has also been documented between children with more openness-to-experience and their likelihood of receiving musical training as young children.


This type of gene-environment correlation can emerge when an individual's genetics causes others to alter their environment. [ 5 ]  For instance, one study on children in  middle childhood  found that a child's innate desire for  autonomy  partially determined the degree of  maternal control  evoked. [ 11 ]


This occurs when individuals seek out environments that are compatible with their  genetic predispositions . [ 5 ]  For example, a person with a genetic predisposition for  athleticism  may be more inclined to choose sports-related activities and environments. [ citation needed ]


Epigenetics  focuses on  cellular  changes in  gene expression  that do not involve changes in  genetic code . [ 12 ]  Epigenetic changes can be a result of cellular mechanisms or environmental factors. One instance of an environment impacting gene expression is  DNA methylation  as a result of  smoking  during  pregnancy . [ 13 ]  Another environmental exposure that can trigger epigenetic changes is  heavy metals  like  arsenic . This is done through the disturbance of  histone acetylation  and DNA methylation which is correlated with increased rates of  cancer ,  autoimmune diseases , and  neurological disorders . [ 14 ]


Epigenetic modifications can affect gene activity independently of DNA sequence modifications. [ 15 ]  Air pollution exposure has been associated with decreased DNA methylation levels which is a process crucial for gene regulation. The effects of air pollution can be seen in the  prenatal  environment as methylation changed in response to the presence of  NO 2  and  NO x , which are forms of air pollution. When exposed to  air pollution , there was a decline in  intrauterine growth . While the mechanism is not fully understood, it could involve the formation of  reactive oxygen species , leading to  oxidative stress  and cellular signaling cascade or increased fetal  cortisol  levels. [ 16 ]  A consequence of altered DNA methylation is  hydroxymethylation , which replaces the  methyl group  with a  hydroxyl group . Hydroxymethylation potentially could disrupt gene expression patterns and contribute to disease development, such as  lung cancer . [ 17 ]  Additionally, exposure to pollutants can exacerbate inflammatory conditions like  asthma  by inducing inflammation in the airways. This leads to increased  cytokine  expression and  immune cell  recruitment. [ 16 ]  Certain pollutants, such as  endocrine-disrupting chemicals (EDC) , interfere with  hormone  signaling pathways and gene expression related to hormone regulation. A certain type of EDC,  bisphenol A  has been linked to changes in gene expression in reproductive tissues and developmental pathways. [ 18 ]


Nutrition  plays a crucial role in shaping gene expression, which can ultimately impact an individual's phenotype. Fetal  malnutrition , for example, has been associated with decreased level DNA methylation, particularly on genes like  IGF2 , which is involved in insulin metabolism. [ 19 ]  The alteration in DNA  methylation  patterns can elevate the risk of developing  metabolic disorders  and type II  diabetes  mellitus. [ 20 ]  Furthermore, prenatal malnutrition can lead to differential DNA methylation of genes related to growth, development, and metabolism. These epigenetic changes increase the likelihood of adverse phenotypes such as  obesity  and  high cholesterol  later in life. [ 21 ]  Malnutrition can also significantly impact gene expression in the  small intestine , leading to alterations in nutrient transporters,  digestive enzymes , barrier function, immune responses, and metabolic adaptation. [ 22 ]  Socioeconomic factors such as  poverty  and  minority status  may exacerbate the effects of malnutrition. Research indicates that individuals that reside in impoverished communities or those who belong to marginalized  racial  and  ethnic  groups may encounter limited access to nutritious food options. [ 23 ]


Physical activity induces epigenetic modifications of specific genes, altering their expression profiles. For example, exercise has been linked to increased methylation of the ASC gene, which typically decreases with age. Methylation can compact a gene, decreasing the amount of protein produced from the gene and the  ASC  gene stimulates  cytokine  production. Thus, the expression of  inflammatory cytokines  decreases. This suppression can help prevent the development of  chronic inflammation  and associated  age-related diseases  due to excess inflammatory cytokines. [ 24 ]  However, these epigenetic modifications depend on the intensity and type of exercise and are reversible with the cessation of physical activity. [ 25 ]  Research shows that exercise for more than six months can have an effect on  telomere  length. Elongation at the ends of chromosomes helps to maintain chromosomal stability and induces epigenetic modifications of specific genes. [ 26 ]


The maternal environment can have epigenetic effects on the developing fetus. For instance,  alcohol  consumed during pregnancy can cross from maternal blood to the placenta and into the fetal environment of the  amniotic cavity , where it can induce epigenetic modifications on fetal DNA. [ 27 ]  Mouse embryo cultures show that alcohol exposure during fetal development can contribute to changes in DNA methylation of genes involved in development, metabolism, and organization of DNA during brain development. [ 28 ]  These alcohol-induced changes in DNA methylation during pregnancy contribute to the distinct set of traits seen in  Fetal Alcohol Spectrum Disorder (FASD) . [ 28 ]  Other instances of prenatal environment impact on fetal epigenetic state include maternal  folic acid ,  stress , and  tobacco smoking  during pregnancy. [ 29 ] [ 30 ] [ 31 ]


Early life stress encompasses parental absence, abuse, and lack of bonding. These stressors during early childhood are associated with epigenetic modifications of the  Hypothalamic-Pituitary-Adrenal (HPA) axis , which mediates the stress response. Using a rat model of maternal care, research has shown that reduced care between mother and offspring is associated with down regulation of  glucocorticoid receptors (GR)  in the  hypothalamus . [ 32 ]  GRs play a critical role in the HPA axis by aiding in the restoration of normal physiological state after stress exposure.  Down regulation  of GRs expression occurs through histone modifications and DNA methylation of the GR gene, resulting in dysregulation of the stress response, including prolonged inflammation and cellular damage. [ 33 ]  Additionally, numerous studies have linked early life stress with later-life  psychiatric disorders , including  anxiety  and  depression , through epigenetic modulation of genes involved in the HPA axis. [ 34 ]  Socioeconomic disparities, discrimination, and cultural factors prevalent within minority communities can contribute to heightened levels of stress and adversity, impacting gene expression and health outcomes. [ 35 ]


Adoption  and  twin studies  are used to investigate the complex interplay between genes and the environment. These studies typically involve the comparison of identical (monozygotic) and fraternal (dizygotic) twins to determine the extent to which genetic factors and environmental influences contribute to variations in traits or behaviors. These studies have contributed to studies of behavior, personality, and psychiatric illnesses. [ 36 ]  For example, a Finnish adoption study on  schizophrenia  revealed that a healthy environment can mitigate the effects of genetics in adopted individuals born to schizophrenic mothers. [ 37 ]  Criminal and  antisocial behavior  have also been found to be influenced by both genetic and environmental factors through these types of studies. [ 38 ] [ 39 ]


Animal models  provide a controlled and manipulable environment in which researchers can investigate the complex interactions between genes and environmental factors, shedding light on various biological and behavioral outcomes.  For example, one study has demonstrated the utility of mouse models in understanding gene-environment interactions in schizophrenia due to the genetic similarities. [ 40 ]


Research on  moths  and  butterflies  has shown that environmental factors like bright sunlight influences their color vision. In environments with more light, they develop more of different  opsins  which allow them to detect light and discern colors. Butterflies depend on color vision to find the correct flowers for their diet and their preferred  habitat . [ 41 ]


Gene-environment interplay has been found to play a part in the majority of diseases. For instance, gene-environment interactions have a prevalent role in mental health disorders; specifically, evidence has found a link to  alcohol dependence , [ 39 ]   schizophrenia , [ 42 ]  and  psychosis . [ 43 ]  The link to alcohol dependence is potentially influenced by a dopamine receptor gene ( DRD2 ) as individuals with the  Taq I allele may have interactions involving this allele and alcohol dependence. [ 39 ]  This interaction is more prevalent when the individual is experiencing higher stress levels. The impacts on psychosis originate from a  single nucleotide polymorphism  (SNP), in the  AKT1  gene.  This causes its carriers who regularly use  cannabis  to be more susceptible to developing psychosis. Additionally, individuals who are homozygous for this particular AKT1 mutation and use cannabis daily are at an increased risk for developing psychotic disorders. [ 43 ]  For schizophrenia, genome-wide by environment interaction studies (GWEIS) and  genome-wide association studies  (GWAS) are used to determine the  loci  at environmental factors used in the determination of GxE. [ 43 ]  Evidence also supports that gene-environment interplay is connected to  cardiovascular  and  metabolic conditions . [ 4 ]  These include roles in  obesity , [ 3 ]   pulmonary disease , [ 44 ]  and  diabetes . [ 45 ]  The rise in the incidence of type II  diabetes  is suggested to be linked to interactions between diet and the  FTO  and   KCNQ1  genes. Mutations within the  KCNQ1  gene affects a pathway that leads to a decrease in  insulin  secretion due to a decline in  pancreatic β cells , but within mice fed a high fat diet enhanced the dysfunction within the pancreatic β cells. [ 45 ]


Genetic redundancy  is a term typically used to describe situations where a given biochemical function is redundantly encoded by two or more  genes . In these cases,  mutations  (or defects) in one of these genes will have a smaller effect on the fitness of the organism than expected from the genes’ function. Characteristic examples of genetic redundancy include (Enns, Kanaoka et al. 2005) and (Pearce, Senis et al. 2004). Many more examples are thoroughly discussed in (Kafri, Levy & Pilpel. 2006).


The main source of genetic redundancy is the process of  gene duplication  which generates multiplicity in gene copy number. A second and less frequent source of genetic redundancy are convergent  evolutionary  processes leading to genes that are close in function but unrelated in sequence (Galperin, Walker & Koonin 1998). Genetic redundancy is typically associated with signaling networks, in which many proteins act together to accomplish teleological functions. In contrast to expectations, genetic redundancy is not associated with gene duplications [Wagner, 2007], neither do redundant genes mutate faster than essential genes [Hurst 1999]. Therefore, genetic redundancy has classically aroused much debate in the context of  evolutionary biology  (Nowak et al., 1997; Kafri, Springer & Pilpel . 2009).


From an evolutionary standpoint, genes with overlapping functions imply minimal, if any,  selective pressures  acting on these genes. One therefore expects that the genes participating in such buffering of mutations will be subject to severe mutational drift diverging their functions and/or expression patterns with considerably high rates. Indeed it has been shown that the  functional divergence  of paralogous pairs in both yeast and human is an extremely rapid process. Taking these notions into account, the very existence of genetic buffering, and the functional redundancies required for it, presents a paradox in light of the evolutionary concepts. On one hand, for genetic buffering to take place there is a necessity for redundancies of gene function, on the other hand such redundancies are clearly unstable in face of natural selection and are therefore unlikely to be found in evolved genomes.


Duplicated genes that diverge in function may undergo  subfunctionalization  or can become   degenerate . When two protein coding genes are degenerate there will be conditions where the gene products appear functionally redundant and also conditions where the gene products take on unique functions.


In  quantitative genetics ,  Q ST  is a statistic intended to measure the degree of  genetic differentiation  among populations with regard to a  quantitative trait . It was developed by Ken Spitze in 1993. [ 1 ]  Its name reflects that Q ST  was intended to be analogous to the  fixation index  for a single  genetic locus  (F ST ). [ 2 ] [ 3 ]  Q ST  is often compared with F ST  of neutral loci to test if variation in a quantitative trait is a result of  divergent selection  or genetic drift, an analysis known as  Q ST –F ST  comparisons .


Q ST  represents the proportion of variance among subpopulations, and is it’s calculation is synonymous to F ST  developed by  Sewall Wright . [ 4 ]  However, instead of using genetic differentiation, Q ST  is calculated by finding the variance of a quantitative trait within and among subpopulations, and for the total population. [ 1 ]  Variance of a quantitative trait among populations (σ 2 GB ) is described as:


σ

 G
 B

 2

 =
 (
 1
 −

 Q

 S
 T

 )

 σ

 T

 2

 {\displaystyle \sigma _{GB}^{2}=(1-Q_{ST})\sigma _{T}^{2}}


And the variance of a quantitative trait within populations (σ 2 GW ) is described as:


σ

 G
 W

 2

 =
 2

 Q

 S
 T

 σ

 T

 2

 {\displaystyle \sigma _{GW}^{2}=2Q_{ST}\sigma _{T}^{2}}


Where σ 2 T  is the total genetic variance in all populations. Therefore, Q ST  can be calculated with the following equation:


Q

 S
 T

 =

 σ

 G
 B

 2

 σ

 G
 B

 2

 +
 2

 σ

 G
 W

 2

 {\displaystyle Q_{ST}={\frac {\sigma _{GB}^{2}}{\sigma _{GB}^{2}+2\sigma _{GW}^{2}}}}


Calculation of Q ST  is subject to several assumptions: populations must be in  Hardy-Weinberg Equilibrium , observed variation is assumed to be due to  additive genetic effects  only, selection and  linkage disequilibrium  are not present, [ 5 ]  and the subpopulations exist within an island model. [ 6 ]


Q ST –F ST  analyses often involve culturing organisms in consistent environmental conditions, known as  common garden experiments , [ 7 ]  and comparing the  phenotypic  variance to genetic variance. If Q ST  is found to exceed F ST , this is interpreted as evidence of divergent selection, because it indicates more differentiation in the trait than could be produced solely by  genetic drift . If Q ST  is less than F ST ,  balancing selection  is expected to be present. If the values of Q ST  and F ST are equivalent, the observed trait differentiation could be due to genetic drift. [ 6 ]


Suitable comparison of Q ST  and F ST  is subject to multiple ecological and evolutionary assumptions, [ 8 ] [ 9 ] [ 10 ]  and since the development of Q ST , multiple studies have examined the limitations and constrictions of Q ST -F ST  analyses. Leinonen et al. notes F ST  must be calculated with neutral loci, however over filtering of non-neutral loci can artificially reduce F ST values. [ 7 ]  Cubry et al. found Q ST  is reduced in the presence of  dominance , resulting in conservative estimates of divergent selection when Q ST  is high, and inconclusive results of balancing selection when Q ST  is low. [ 5 ]  Additionally,  population structure  can significantly impact Q ST -F ST  ratios. Stepping stone models, which can generate more evolutionary noise than island models, are more likely to experience  type 1 errors . [ 6 ]  If a subset of populations act as sources, such as during  invasion , weighting the genetic contributions of each population can increase detection of adaptation. [ 11 ]  In order to improve precision of Q ST  analyses, more populations (>20) should be included in analyses. [ 12 ]


Multiple studies have incorporated Q ST  to separate effects of  natural selection  and genetic drift, and Q ST  is often observed to exceed F ST , indicating local adaptation. [ 13 ]  In an  ecological restoration  study, Bower and Aitken used Q ST  to evaluate suitable populations for seed transfer of  whitebark pine . They found high Q ST  values in many populations, suggesting local adaptation for cold-adapted characteristics. [ 14 ]  During an assessment of the invasive species,  Brachypodium sylvaticum , Marchini et al. found divergence between native and invasive populations during initial establishment in the invaded range, but minimal divergence during  range expansion . [ 11 ]  In an examination of the common snapdragon ( Antirrhinum majus ) along an elevation gradient, Q ST -F ST  analyses revealed different adaptation trends between two  subspecies  ( A. m. pseudomajus  and  A. m. striatum ). While both subspecies occur at all elevations,  A. m. striatum  had high Q ST  values for traits associated with altitude adaptation: plant height, number of branches, and internode length.  A. m. pseudomajus  had lower Q ST  than F ST  values for germination time. [ 15 ]


In the field of  molecular biology ,  trans -acting  ( trans -regulatory,  trans -regulation), in general, means "acting from a different molecule" ( i.e. ,  intermolecular ).  It may be considered the opposite of  cis -acting  ( cis -regulatory,  cis -regulation), which, in general, means "acting from the same molecule" ( i.e. ,  intramolecular ).


In the context of  transcription  regulation, a  trans -acting factor  is usually a regulatory  protein  that binds to  DNA . [ 1 ]   The binding of a  trans -acting factor to a  cis -regulatory element in  DNA  can cause changes in transcriptional expression levels.   microRNAs  or other diffusible molecules are also examples of  trans -acting factors that can regulate target sequences. [ 2 ]
The  trans -acting gene may be on a different  chromosome  to the target gene, but the activity is via the intermediary protein or RNA that it encodes.   Cis -acting  elements, on the other hand, do not code for protein or RNA.  Both the  trans -acting gene and the protein/RNA that it encodes are said to "act in  trans " on the target gene.


Transcription factors  are categorized as trans-acting factors.


Antigenic escape ,  immune escape ,  immune evasion  or  escape mutation  occurs when the  immune system  of a  host , especially of a human being, is unable to respond to an  infectious agent : the host's immune system is no longer able to recognize and eliminate a  pathogen , such as a  virus . This process can occur in a number of different ways of both a genetic and an environmental nature. [ 1 ]  Such mechanisms include  homologous recombination , and manipulation and resistance of the host's immune responses. [ 2 ]


Different  antigens  are able to escape through a variety of mechanisms. For example, the African  trypanosome  parasites are able to clear the host's  antibodies , as well as resist  lysis  and inhibit parts of the  innate immune response . [ 3 ]  A bacterium,  Bordetella pertussis , is able to escape the immune response by inhibiting  neutrophils  and  macrophages  from invading the infection site early on. [ 4 ]  One cause of antigenic escape is that a pathogen's  epitopes  (the binding sites for  immune cells ) become too similar to a person's naturally occurring  MHC-1  epitopes, resulting in the immune system becoming unable to distinguish the infection from self-cells. [ citation needed ]


Antigenic escape is not only crucial for the host's natural immune response, but also for the resistance against  vaccinations . The problem of antigenic escape has greatly deterred the process of creating new vaccines. Because vaccines generally cover a small ratio of strains of one virus, the recombination of antigenic DNA that lead to diverse pathogens allows these invaders to resist even newly developed vaccinations. [ 5 ]  Some antigens may even target pathways different from those the vaccine had originally intended to target. [ 4 ]  Recent research on many vaccines, including the  malaria  vaccine, has focused on how to anticipate this diversity and create vaccinations that can cover a broader spectrum of  antigenic variation . [ 5 ]  On 12 May 2021, scientists reported to  The United States Congress  of the continuing threat of  COVID-19 variants  and COVID-19 escape mutations, such as the  E484K  virus mutation. [ 6 ]


The most common of antigenic escape mechanisms,  homologous recombination , can be seen in a wide variety of bacterial pathogens, including  Helicobacter pylori , a bacterium that infects the  human stomach . While a host's homologous recombination can act as a defense mechanisms for fixing  DNA double stranded breaks  (DSBs), it can also create changes in antigenic DNA that can create new, unrecognizable proteins that allow the  antigen  to escape recognition by the host's immune response. Through the recombination of  H. pylori's   outer membrane proteins ,  immunoglobulins  can no longer recognize these new structures and, therefore, cannot attack the antigen as part of the normal immune response. [ 2 ]


African  trypanosomes  are  parasites  that are able to escape the immune responses of its host animal through a range of mechanisms. Its most prevalent mechanism is its ability to evade recognition by antibodies through  antigenic variation . This is achieved through the switching of its  variant surface glycoprotein  or VSG, a substance that coats the entire antigen. When this coat is recognized by an antibody, the parasite can be eliminated. However, variation of this coat can lead to antibodies being unable to recognize and eliminate the antigen. In addition to this, the VSG coat is able to clear the antibodies themselves to escape their clearing function. [ citation needed ] [ clarification needed ]


Trypanosomes are also able to achieve evasion through the mediation of the host's immune response. Through the conversion of  ATP  to  cAMP  by the enzyme  adenylate cyclase , the production of  TNF-α , a signaling  cytokine  important for inducing inflammation, is inhibited in  liver   myeloid cells . In addition, trypanosomes are able to weaken the immune system by inducing  B cell   apoptosis  (cell death) and the degradation of B cell  lymphopoiesis . They are also able to induce suppressor molecules that can inhibit  T cell  reproduction. [ 3 ]


Lafforgue et al 2011 found escape mutants in  plant RNA viruses  to be encouraged by coexistence of  transgenic crops  with  artificial microRNA (amiR) -based resistance with fully susceptible individuals of the same crop, and even more so by coexistence with weakly amiR-producing transgenics. [ 7 ] [ 8 ] [ 9 ] [ 10 ]


Many  head and neck cancers  are able to escape immune responses in a variety of ways. One such example is through the production of pro-inflammatory and  immunosuppressive  cytokines. This can be achieved when the tumor recruits immunosuppressive cell subsets into the tumor's environment. Such cells include pro-tumor M2 macrophages,  myeloid-derived suppressor cells  (MDSCs), Th-2 polarized  CD4 T-lymphocytes , and  regulatory T-lymphocytes . These cells can then limit the responses of T cells through the production of cytokines and by releasing immune-modulating  enzymes . [ 1 ]   Additionally tumors can escape antigen-directed therapies by loss or down-regulation of the associated antigens, as well demonstrated after checkpoint blockade immunotherapy [ 11 ]  and CAR-T cell therapy [ 12 ]  though more recent data indicate that this may be prevented by localized bystander killing mediated by fasL/fas. [ 13 ]   Alternatively therapies can be developed to encompass multiple antigens in parallel. [ 14 ]


While vaccines are created to strengthen the immune response to  pathogens , in many cases these vaccines are not able to cover the wide variety of strains a pathogen may have. Instead they may only protect against one or two strains, leading to the escape of strains not covered by the vaccine. [ 5 ]  This results in the pathogens being able to attack targets of the immune system different than those intended to be targeted by the vaccination. [ 4 ]  This parasitic antigen diversity is particularly troublesome for the development of the  malaria vaccines . [ 5 ]


In order to solve this problem, vaccines must be able to cover the wide variety of strains within a bacterial population. In recent research of  Neisseria meningitidis , the possibility of such broad coverage may be achieved through the combination of multi-component  polysaccharide  conjugate vaccines. However, in order to further improve upon broadening the scope of vaccinations, epidemiological surveillance must be conducted to better detect the variation of escape mutants and their spread. [ 4 ]


Genetics  is the study of  genes  and tries to explain what they are and how they work. Genes are how living  organisms  inherit features or  traits  from their ancestors; for example, children usually look like their parents because they have inherited their parents' genes. Genetics tries to identify which traits are inherited and to explain how these traits are passed from generation to generation.


Some traits are part of an organism's  physical appearance , such as  eye   color  or height. Other sorts of traits are not easily seen and include  blood types  or resistance to  diseases . Some traits are inherited through genes, which is the reason why tall and thin people tend to have tall and thin children. Other traits come from interactions between genes and the environment, so a child who inherited the tendency of being tall will still be short if  poorly   nourished . The way our genes and environment interact to produce a trait can be complicated. For example, the chances of somebody dying of  cancer  or  heart disease  seems to depend on both their genes and their lifestyle.


Genes are made from a long  molecule  called  DNA , which is copied and inherited across generations. DNA is made of  simple units  that line up in a particular order within it, carrying genetic information. The language used by DNA is called  genetic code , which lets organisms read the information in the genes. This information is the instructions for the construction and operation of a living organism.


The information within a particular gene is not always exactly the same between one organism and another, so different copies of a gene do not always give exactly the same instructions. Each unique form of a single gene is called an  allele . As an example, one allele for the gene for hair color could instruct the body to produce much pigment, producing black hair, while a different allele of the same gene might give garbled instructions that fail to produce any pigment, giving white hair.  Mutations  are random changes in genes and can create new alleles. Mutations can also produce new traits, such as when mutations to an allele for black hair produce a new allele for white hair. This appearance of new traits is important in  evolution .


Genes are pieces of DNA that contain information for the synthesis of  ribonucleic acids  (RNAs) or  polypeptides . Genes are inherited as units, with two parents dividing out copies of their genes to their offspring. Humans have two copies of each of their genes, but each  egg  or  sperm  cell only gets  one  of those copies for each gene. An egg and sperm join to form a  zygote  with a complete set of genes. The resulting offspring has the same number of genes as their parents, but for any gene, one of their two copies comes from their father and one from their mother. [ 1 ]


The effects of mixing depend on the types (the  alleles ) of the gene. If the father has two copies of an allele for red hair, and the mother has two copies for brown hair, all their children get the two alleles that give different instructions, one for red hair and one for brown. The hair color of these children depends on how these alleles work together. If one allele  dominates  the instructions from another, it is called the  dominant  allele, and the allele that is overridden is called the  recessive  allele. In the case of a daughter with alleles for both red and brown hair, brown is dominant and she ends up with brown hair. [ 2 ]


Although the red color allele is still there in this brown-haired girl, it doesn't show. This is a difference between what is seen on the surface (the traits of an organism, called its  phenotype ) and the genes within the organism (its  genotype ). In this example, the allele for brown can be called "B" and the allele for red "b". (It is normal to write dominant alleles with capital letters and recessive ones with lower-case letters.) The brown hair daughter has the "brown hair phenotype" but her genotype is Bb, with one copy of the B allele, and one of the b allele.


Now imagine that this woman grows up and has children with a brown-haired man who also has a Bb genotype. Her eggs will be a mixture of two types, one sort containing the B allele, and one sort the b allele. Similarly, her partner will produce a mix of two types of sperm containing one or the other of these two alleles. When the transmitted genes are joined up in their offspring, these children have a chance of getting either brown or red hair, since they could get a genotype of BB = brown hair, Bb = brown hair or bb = red hair. In this generation, there is, therefore, a chance of the recessive allele showing itself in the phenotype of the children—some of them may have red hair like their grandfather. [ 2 ]


Many traits are inherited in a more complicated way than the example above. This can happen when there are several genes involved, each contributing a small part to the result. Tall people tend to have tall children because their children get a package of many alleles that each contribute a bit to how much they grow. However, there are not clear groups of "short people" and "tall people", like there are groups of people with brown or red hair. This is because of the large number of genes involved; this makes the trait very variable and people are of many different heights. [ 3 ]  Despite a common misconception, the green/blue eye traits are also inherited in this complex inheritance model. [ 4 ]  Inheritance can also be complicated when the trait depends on the interaction between genetics and environment. For example, malnutrition does not change traits like eye color, but can stunt growth. [ 5 ]


The function of genes is to provide the information needed to make molecules called  proteins  in cells. [ 1 ]  Cells are the smallest independent parts of organisms: the human body contains about 100 trillion cells, while very small organisms like  bacteria  are just a single cell. A cell is like a miniature and very complex factory that can make all the parts needed to produce a copy of itself, which happens when cells  divide . There is a simple division of labor in cells—genes give instructions and proteins carry out these instructions, tasks  like building a new copy of a cell, or repairing the damage. [ 6 ]  Each type of protein is a specialist that only does one job, so if a cell needs to do something new, it must make a new protein to do this job. Similarly, if a cell needs to do something faster or slower than before, it makes more or less of the protein responsible. Genes tell cells what to do by telling them which proteins to make and in what amounts.


Proteins are made of a chain of 20 different types of  amino acid  molecules. This chain folds up into a compact shape, rather like an untidy ball of string. The shape of the protein is determined by the sequence of amino acids along its chain and it is this shape that, in turn, determines what the protein does. [ 6 ]  For example, some proteins have parts of their surface that perfectly match the shape of another molecule, allowing the protein to bind to this molecule very tightly. Other proteins are  enzymes , which are like tiny machines that alter other molecules. [ 7 ]


The information in DNA is held in the sequence of the repeating units along the DNA chain. [ 8 ]  These units are four types of  nucleotides  (A, T, G and C) and the sequence of nucleotides stores information in an alphabet called the  genetic code . When a gene is read by a cell the DNA sequence is copied into a very similar molecule called  RNA  (this process is called  transcription ). Transcription is controlled by other DNA sequences (such as  promoters ), which show a cell where genes are, and control how often they are copied. The RNA copy made from a gene is then fed through a structure called a  ribosome , which translates the sequence of nucleotides in the RNA into the correct sequence of amino acids and joins these amino acids together to make a complete protein chain. The new protein then folds up into its active form. The process of moving information from the language of RNA into the language of amino acids is called  translation . [ 9 ]


If the sequence of the nucleotides in a gene changes, the sequence of the amino acids in the protein it produces may also change—if part of a gene is deleted, the protein produced is shorter and may not work anymore. [ 6 ]  This is the reason why different alleles of a gene can have different effects on an organism. As an example, hair color depends on how much of a dark substance called  melanin  is put into the hair as it grows. If a person has a normal set of the genes involved in making melanin, they make all the proteins needed and they grow dark hair. However, if the alleles for a particular protein have different sequences and produce proteins that can't do their jobs, no melanin is produced and the person has white skin and hair ( albinism ). [ 10 ]


Genes are copied each time a cell divides into two new cells. The process that copies DNA is called  DNA replication . [ 8 ]  It is through a similar process that a child inherits genes from its parents when a copy from the mother is mixed with a copy from the father.


DNA can be copied very easily and accurately because each piece of DNA can direct the assembly of a new copy of its information. This is because DNA is made of two strands that pair together like the two sides of a zipper. The nucleotides are in the center, like the teeth in the zipper, and pair up to hold the two strands together. Importantly, the four different sorts of nucleotides are different shapes, so for the strands to close up properly, an  A  nucleotide must go opposite a  T  nucleotide, and a  G  opposite a  C . This exact pairing is called  base pairing . [ 8 ]


When DNA is copied, the two strands of the old DNA are pulled apart by enzymes; then they pair up with new nucleotides and then close. This produces two new pieces of DNA, each containing one strand from the old DNA and one newly made strand. This process is not predictably perfect as proteins attach to a nucleotide while they are building and cause a change in the sequence of that gene. These changes in the DNA sequence are called  mutations . [ 11 ]  Mutations produce new alleles of genes. Sometimes these changes stop the functioning of that gene or make it serve another advantageous function, such as the melanin genes discussed above. These mutations and their effects on the traits of organisms are one of the causes of  evolution . [ 12 ]


A population of organisms evolves when an inherited trait becomes more common or less common over time. [ 12 ]  For instance, all the mice living on an island would be a single population of mice: some with white fur, some gray. If over generations, white mice became more frequent and gray mice less frequent, then the color of the fur in this population of mice would be  evolving . In terms of genetics, this is called an increase in  allele frequency .


Alleles become more or less common either by chance in a process called  genetic drift  or by  natural selection . [ 13 ]  In natural selection, if an allele makes it more likely for an organism to survive and reproduce, then over time this allele becomes more common. But if an allele is harmful, natural selection makes it less common. In the above example, if the island were getting colder each year and snow became present for much of the time, then the allele for white fur would favor survival since predators would be less likely to see them against the snow, and more likely to see the gray mice. Over time white mice would become more and more frequent, while gray mice less and less.


Mutations create new alleles. These alleles have new DNA sequences and can produce proteins with new properties. [ 14 ]  So if an island was populated entirely by black mice, mutations could happen creating alleles for white fur. The combination of mutations creating new alleles at random, and natural selection picking out those that are useful, causes an  adaptation . This is when organisms change in ways that help them to survive and reproduce. Many such changes, studied in  evolutionary developmental biology , affect  the way the embryo develops  into an adult body.


Some diseases are hereditary and run in families; others, such as  infectious diseases , are caused by the environment. Other diseases come from a combination of genes and the environment. [ 15 ]   Genetic disorders  are diseases that are caused by a single allele of a gene and are inherited in families. These include  Huntington's disease ,  cystic fibrosis  or  Duchenne muscular dystrophy . Cystic fibrosis, for example, is caused by mutations in a single gene called  CFTR  and is inherited as a recessive trait. [ 16 ]


Other diseases are influenced by genetics, but the genes a person gets from their parents only change their risk of getting a disease. Most of these diseases are inherited in a complex way, with either multiple genes involved, or coming from both genes and the environment. As an example, the risk of  breast cancer  is 50 times higher in the families most at risk, compared to the families least at risk. This variation is probably due to a large number of alleles, each changing the risk a little bit. [ 17 ]  Several of the genes have been identified, such as  BRCA1  and  BRCA2 , but not all of them. However, although some of the risks are genetic, the risk of this cancer is also increased by being overweight, heavy alcohol consumption and not exercising. [ 18 ]  A woman's risk of breast cancer, therefore, comes from a large number of alleles interacting with her environment, so it is very hard to predict.


Since traits come from the genes in a cell, putting a new piece of DNA into a cell can produce a new trait. This is how  genetic engineering  works. For example, rice can be given genes from a maize and a soil bacteria so the rice produces  beta-carotene , which the body converts to vitamin A. [ 19 ]  This can help children with Vitamin A deficiency. Another gene being put into some crops comes from the bacterium  Bacillus thuringiensis ; the gene makes a protein that is an  insecticide . The insecticide kills insects that eat the plants but is harmless to people. [ 20 ]  In these plants, the new genes are put into the plant before it is grown, so the genes are in every part of the plant, including its seeds. [ 21 ]  The plant's offspring inherit the new genes, which has led to concern about the spread of new traits into wild plants. [ 22 ]


The kind of technology used in genetic engineering is also being developed to treat people with  genetic disorders  in an experimental medical technique called  gene therapy . [ 23 ]  However, here the new, properly working gene is put in targeted cells, not altering the chance of future children inheriting the disease causing alleles.


The following  outline  is provided as an overview of and topical guide to genetics:


Genetics  –  science  of  genes ,  heredity , and  variation  in living  organisms . [ 1 ] [ 2 ]  Genetics deals with the  molecular structure and function  of genes, and gene behavior in  context of a  cell  or  organism  (e.g.  dominance  and  epigenetics ),  patterns of inheritance from parent to offspring, and  gene distribution, variation and change in  populations .


History of genetics


The  Absconditabacterales genetic code  (tentative code number 37) translates UGA to glycine, and CGG and GCA to tryptophan, as determined by the codon assignment software Codetta; [ 1 ]  it was further shown that these recodings are associated with three special tRNAs with appropriate anticodons and tRNA identity elements. Codetta called the Absconditibacterales code (sometimes leaving the rare CGA codon uncalled) for the following genome assemblies: GCA_002792495.1, GCA_001007975.1, GCA_003488625.1, GCA_003260355.1, GCA_003242865.1, GCA_000350285.1, GCA_002746475.1, GCA_007116275.1, GCA_007115995.1, GCA_002361595.1, GCA_000503875.1, GCA_003543185.1, GCA_002441085.1, and GCA_002791215.1. Review of the GTDB taxonomy system [ 2 ]  (release 220) for the order Absconditabacterales (phylum Patescibacteria) left two questionable genome assemblies (GCA_002414185.1, for which Codetta had called the CGA codon Arg, and GCA_937862565.1, the only known genome from the CALMFT01 family and untested by Codetta); spot-checking these two genomes shows that they both have all three special tRNAs, suggesting that the code is universal across the order.


Ac/Ds transposable controlling elements  was the first  transposable element  system recognized in  maize . The  Ac Activator  element is autonomous, whereas the  Ds Dissociation  element requires an  Activator  element to transpose. [ 1 ]   Ac  was initially discovered as enabling a  Ds  element to break  chromosomes . Both  Ac  and  Ds  can also insert into genes, causing  mutants  that may revert to normal on excision of the element. [ 2 ]  The phenotypic consequence of  Ac / Ds  transposable element includes  mosaic colors in kernels and leaves in maize .


Its discovery was based on studying its genetic behavior, i.e., "jumping genes" in maize and published by  Barbara McClintock , [ 3 ] [ 4 ]  leading to her 1983  Nobel Prize in Medicine . The Ac/Ds transposable elements were first isolated and sequenced By Fedoroff et al. 1983  [ 5 ]  using insertions of  Ac  and  Ds  into the well-studied  Waxy(Wx1)  gene. The elements have been shown to function in other plants, including tobacco, [ 6 ]  Arabidopsis, [ 7 ] ) and rice. [ 8 ]


Genomic analysis of maize show that these elements, which share terminal 11 bp imperfect  inverted repeat  sequences, have much sequence heterogeneity, both in length and content. They also include a class of DNA elements that do not transpose in the presence of the Ac element (Du et al. 2011). The chromosome breaking property has been shown to come from pairs of closely positioned elements. [ 9 ]


Researchers use mutant phenotypes to discover gene functions. Ac/Ds prefer to transpose to nearby genes, affording a way to mutagenize those regions of the genome, and by subsequent genetic crosses, remove the Ac that causes new mutants and instability of a Ds mutant. Collections of Ac/Ds elements that cover the genome and are useful for generating mutants. [ 10 ]  Application of Ac/Ds toolkits has also been applied to other species like arabidopsis, yeast, and even zebrafish. [ 1 ]


Activator (Ac)/ Dissociation (Ds) transposable elements were discovered by Barbara McClintock when she was studying the maize genomic composition of the short arm of chromosome 9. She noticed that when chromosome 9 had been exposed to drastic structural modifications, the progeny had changes such as multiple copies of the short arm or lacking one or more of its parts, as well as other changes. She believed that these changes were due to transposition of “mutable loci” into the genome and that these spontaneous translocations were not random due to where the breaks occurred and where they fused. [ 2 ]


Ac/Ds elements have been observed to insert into gene rich regions of the maize genome, they alter the regulation of gene expression and may create unstable insertion alleles, stable derivatives, or excision alleles due to insertion of a transposable element into a gene. [ 11 ]  Transposable elements residing at or near a gene prevent gene expression and can also result in a mutation that causes exhibition of the recessive phenotype. [ 12 ]  Removal of transposable element locus results in restoration of the gene organization and activity. [ 2 ]  Ac is 4565 base pairs long and codes for a 3.5 kb open reading frame that synthesizes an 807 amino acid long transposase enzyme. [ 11 ]  Ac elements are autonomous and their movement results in a 4.3 kb insertion. [ 13 ]  Ds elements are not autonomous because they cannot produce the transposase needed for transposition, and can only transpose when it is provided by the Ac element. [ 13 ]  Ds elements have shown to cause a 4.1kB and 2.0 kB insertions. [ 13 ]  The transposable elements were seen in progeny of plants that had undergone stress, and mutations caused by the insertion are like those caused by x-rays, UV light, or chemicals causing events like chromosome breakage and fusion. [ 2 ]


There are distinct families of transposon controlling elements that are made up of a combination of elements some that can, and some that cannot, transpose. The families differ in their developmental timing and transposition frequency, as well other types of genetic rearrangements. [ 13 ]  Ac or Ds element insertion near a locus causes unstable mutations. Ds elements are considered non-autonomous because they cannot transpose without the presence of the Ac element, since they themselves cannot produce the enzyme transposase needed for transposition. However, since Ds elements can utilize the transposase enzyme produced by the Ac elements, it shows that they have the structural information needed for transposition and only lack the information needed to produce the enzyme. Ds elements were identified at the site of a chromosome breakage. [ 2 ]  Ac and Ds elements are structurally related because insertion of either element brings about similar mutations. They are also similar because their restriction endonuclease cleavage site maps are indistinguishable from each other. [ 13 ]


Different mutants display different levels of gene expression, which largely depends on the presence or absence of the transposable element somewhere else in the genome. [ 12 ]  The different function of the elements are detected as altered temporal or spatial patterns of somatic reversions or reversible inactivation of the entire element. [ 12 ]  Some excision events of these elements restore gene function and can be detected as somatic reversions. [ 12 ]  If Ac or Ds insertions in an exon, and the transposable elements are excised leaving some of the duplicated base pairs behind, it alters the protein structure either by causing mutations  such as frame shift mutations or the addition of amino acids. [ 12 ]  In some cases, unstable Ds or Ac induced mutant can give rise to a stable recessive mutant. [ 12 ]  Ac determines the mutation process and the mutable loci as well as their timing. [ 2 ]  Ac transposase does not influence transcription initiation site selection, and large numbers of Ac elements may inhibit the expression of Ds by reducing the rate of transcription initiation instead of affecting the transcription site selection. [ 11 ]  Ac transposase is also capable of suppressing gene expression when Ac or Ds inserts in 5’ untranslated region using target sites. [ 11 ]  Ac or Ds element insertion sites have been characterized by the presence of different direct duplications of 6-10 base pairs prior to insertions, indicating that Ac transposase may have preference for short duplication as insertion sites. [ 12 ]  Transposition of both Ac and Ds occurs during development of a tissue and is under precise control which is determined by the number of Ac loci present, their organization, and their position in the chromosome complement. [ 2 ]  The transposable elements not only entirely remove or alter the gene function via insertion, but can also exert a mutator activity when they leave the position where they had visited the chromosome. [ 12 ]  Induced disturbances in quantity and organization of the heterochromatic elements of the chromosome could give rise to a series of alterations in its structure, behavior, and in genic reactions that can alter phenotypic expression. [ 2 ]


The Ac and Ds elements share two properties that are common for transposable elements. [ 12 ]  One is that at the site of their insertion, a short DNA sequence is 8 base pairs long, and is duplicated and borders exactly at the Ac or Ds sequence. [ 12 ]  Second, the sequences of several Ds elements terminate in an inverted repeat of the nucleotide sequence TAGGATGAAA. [ 12 ]  The Ds elements shows quite some degree of similarity with the Ac elements, such as the Ds9 element which is a complemental mutant of Ac and only differs in the open reading frame 1. [ 12 ]  Other Ds elements differ from the Ac element by internal deletions. [ 12 ]


As Ac copy number increases, the expression of genes flanking the Ds promoter insertion are negatively regulated, which is called the negative dosage effect. [ 14 ]  Ds flanking gene expression is inhibited in the presence of the autonomous Ac element. [ 11 ]  As the Ac element copy number increases, transposition events that require Ac occur at a later time during endosperm development. [ 14 ]  Ac causes no or few chromosome breaks.  In the absence of Ac, Ds caused mutations are stable. [ 12 ]  By identifying alleles that suppress the Ac element they could be used for functional genomics studies. [ 11 ]  The properties of transposable elements can also be altered in a clonally heritable fashion. [ 12 ]  Ds elements can be used as building blocks for complicated structures like the double Ds or the 30kb transposon-like insertion which is terminated by Ds elements. [ 12 ]  Ds elements can generate long direct inverted duplicates of a chromosome segment, indicating that Ds elements are able to mobilize DNA sequences unrelated to themselves, this can provide a mechanism for rearrangement of genetic information. [ 12 ]  Since small duplication of host DNA created by the insertion of the elements are left over in a slightly altered form after excision of the transposable element, they may indicate that plant transposable elements play a role in the evolution of genes. [ 12 ]


Accessory gene regulator (agr)  is a complex 5  gene locus  that is a global  regulator  of  virulence  in  Staphylococcus aureus . [ 1 ] [ 2 ] [ 3 ]  It encodes a two-component transcriptional  quorum-sensing  (QS) system activated by an autoinducing, thiolactone-containing cyclic peptide (AIP). [ 4 ]


Agr occurs in 4 allelic subtypes that have an important role in staphylococcal evolution. [ 5 ] [ 6 ]  The corresponding AIPs are mutually cross-inhibitory, which may enhance the evolutionary separation of the 4 groups. [ 6 ] [ 7 ]  The  agr  receptor, AgrC, is a model histidine phosphokinase (HPK) that has been used to decipher the molecular mechanism of  signal transduction . [ 8 ]  AIP binding to the extracellular domain of AgrC causes twisting of the intracellular a-helical domain so as to enable trans-phosphorylation of the active site histidine;  the inhibitory AIPs cause the α-helical domain to twist in the opposite direction, preventing trans-phosphorylation. [ 8 ]  The  agr  QS circuit autoactivates transcription of  agrA  which, in turn upregulates the phenol-souble modulins. [ 9 ]  More importantly, it activates transcription of a divergently oriented promoter whose transcript, known as  RNAIII , [ 10 ]  is a 514 nt regulatory RNA that encodes δ-hemolysin and is the major effector of the  agr  regulon. [ 10 ]   RNAIII  acts by  antisense  inhibition or activation of target gene translation. In vitro, early in growth, genes encoding surface proteins important for adhesion and immune evasion (such as  spa  – encoding protein A [ 11 ] ) are expressed, enabling the organism to gain a foothold. Later in growth, these genes are down-regulated by  RNAIII  and those encoding toxins, hemolysins and other virulence-related proteins, are turned on, enabling the organism to establish and promulgate its pathological programs, such as abscess formation. [ 12 ]  It is assumed that this program operates in vivo as well. As  agr  is essential for staphylococcal contagion, [ 13 ]   agr- defective mutants are not contagious, but enable the organism's long-term survival in chronic conditions such as surgical implant infections,  osteomyelitis  or the infected lung in  cystic fibrosis . In keeping with this behavior, mutations inactivating  agr  function enhance the stability of  biofilms , [ 14 ]  which are key to the maintenance of chronic infections.


Agr  is widely conserved among  Bacillota [ 15 ]  and has a well-defined role in virulence regulation in several genera, especially  Listeria  and  Clostridia .


The agouti gene, the   Agouti-signaling protein  (ASIP) is responsible for variations in color in many species.  Agouti  works with  extension  to regulate the color of  melanin  which is produced in hairs. The agouti protein causes red to yellow pheomelanin to be produced, while the competing molecule  α-MSH  signals production of brown to black eumelanin. In wildtype mice, alternating cycles of agouti and α-MSH production cause  agouti coloration . Each hair has bands of yellow which grew during agouti production, and black which grew during α-MSH production. Wildtype mice also have light-colored bellies. The hairs there are a creamy color the whole length because the agouti protein was produced the whole time the hairs were growing. [ 1 ] [ 2 ]


In mice and other species, loss of function mutations generally cause a darker color, while gain of function mutations cause a yellower coat. [ 3 ]


As of 1979, there were 17 known alleles of agouti in mice. [ 4 ]


This is not a complete list of mouse agouti alleles.


The nonagouti allele  a  is unusually likely to revert to the black-and-tan allele  a t  or to the white-bellied agouti allele  A W . [ 5 ]


Agouti production is regulated by multiple different promoter regions, capable of promoting transcription just in the ventral (belly) area, as seen in white-bellied agouti and black-and-tan mice, or all across the body but just during a specific part of the hair growth cycle, as seen in agouti and white-bellied agouti. [ 6 ]


Lethal yellow and viable yellow cause  obesity , features of type II  diabetes , and a higher likelihood of tumors. [ 2 ]  In normal mice  Agouti  is only expressed in the skin during hair growth, but these dominant yellow mutations cause it to be expressed in other  tissues  including  liver ,  muscle , and  fat . [ 7 ]  The  mahogany  locus interacts with  Agouti  and a mutation there can override the pigmentation and body weight effects of lethal yellow. [ 8 ]


Viable yellow agouti mice can inherit epigenetic differences from their dam affecting how yellow or brown they become. [ 9 ]


The mouse agouti gene is found on chromosome 2. [ 2 ]


In  dogs , the agouti gene is associated with various coat colors and patterns. [ 10 ]


The alleles at the A locus are related to the production of agouti-signaling protein (ASIP) and determine whether an animal expresses an  agouti  appearance and, by controlling the distribution of pigment in individual hairs, what type of agouti. There are four known alleles that occur at the A locus:


Most texts suggest that the dominance hierarchy for the A locus alleles appears to be as follows:  A y  > a w  > a t  > a ; however, research suggests the existence of pairwise dominance/recessiveness relationships in different families and not the existence of a single hierarchy in one family. [ 16 ]


A 2021 study found distinct genetic causes for fawn and sable, which it refers to as "dominant yellow" and "shaded yellow". Both have a more active hair cycle promoter than the wildtype agouti, but dominant yellow also has a more active ventral promoter. The hair cycle promoter involved in these colors is thought to have arisen about 2 million years ago in an extinct species of canid, which later hybridized with wolves. [ 17 ]


The dominant, wild-type  A  allows hairs to be banded with black and red (revealing the underlying  tabby  pattern), while the recessive  non-agouti  or "hypermelanistic" allele,  a , causes black pigment production throughout the growth cycle of the hair. [ 18 ]  Thus, the non-agouti genotype (aa) masks or hides the tabby pattern, although sometimes a suggestion of the underlying pattern can be seen (called "ghost striping"), especially in kittens. The sex-linked orange coloration is  epistatic  over agouti, and prevents the production of black pigment.


In normal horses,  ASIP  restricts the production of eumelanin to the "points": the legs, mane, tail, ear edges, etc. [ 21 ]  In 2001, researchers discovered a recessive mutation on  ASIP  that, when homozygous, left the horse without any functional ASIP. As a result, horses capable of producing true black pigment had uniformly black coats. [ 22 ]  The dominant,  wildtype   allele  producing  bay  is symbolized as  A , while the  recessive  allele producing  black  is symbolized as  a .  Extension  is  epistatic  over  agouti  and will cause  chestnut  coloration regardless of what  agouti  alleles are present.


The cause behind the various shades of bay, particularly the genetic factors responsible for wild bay and  seal brown , have been contested for over 50 years. In 1951, zoologist  Miguel Odriozola  published "A los colores del caballo" in which he suggested four possible alleles for the "A" gene,  A+ ,  A ,  A t , and  a , in order of most dominant to least. [ 23 ]


This was accepted until the 1990s, when a different hypothesis became popular. [ 24 ]  It proposed that shades of bay were caused by many different genes, some which lightened the coat, some which darkened it. This theory also suggested that seal brown horses were black horses with a trait called  pangare . [ 25 ]  Pangaré is an ancestral trait also called "mealy", which outlines the soft or communicative parts of the horse in buff tan.


The combination of black and pangaré was dismissed as the cause of seal brown in 2001, when a French research team published  Mutations in the agouti (ASIP), the extension (MC1R), and the brown (TYRP1) loci and their association to coat color phenotypes in horses (Equus caballus) . This study used a DNA test to identify the recessive  a  allele on the Agouti locus, and found that none of the horses fitting the phenotype of seal brown were homozygous for the  a  allele. [ 22 ] [ 26 ]


In 2007 one genetics lab began offering a test for what they believed was a marker for seal brown, and later for an agouti allele which they believed caused the brown color. [ 27 ] [ 28 ]  However, the underlying research was never published and the test was suspended by 2015 due to unreliable results. [ 29 ] [ 30 ]


The genetic alleles that create seal brown and wildtype bay remain unknown. It is still hypothesized that to some extent, the darkening of coat color in some bays may be regulated by unrelated genes for traits like " sooty ". [ 31 ]


Most donkeys have creamy to gray-white areas on the belly and around the muzzle and eyes, called light  points  or  pangare . However, a recessive variant of agouti causes those areas to be the same color as the body in a pattern called no light points or NLP, which is similar to recessive black in other mammals. This allele can be found in  Norman donkeys  and American  miniature donkeys . [ 32 ]


In rabbits, the wildtype is agouti with a light belly, and a recessive non-agouti allele causes a black coat. A third allele, possibly a mutation to a regulator or promoter region, is thought to cause black and tan color. The nonagouti allele is estimated to have first appeared before 1700. [ 3 ]


Agouti  is linked to the  wideband  gene, with about a 30% crossover rate. [ 33 ]


Like white bellied agouti mice, rabbits with wildtype agouti produce transcripts with different untranslated 5' ends that have different dorsal and ventral expression. The 1A exon is only expressed in the belly region and may be responsible for the lighter color there. [ 3 ]


The  agricultural weed syndrome  is the set of common traits which make a plant a successful agricultural  weed . [ 1 ] [ 2 ] [ 3 ]  Most of these traits are not, themselves,  phenotypes  but are instead methods of rapid  adaptation . So equipped, plants of various origins - invasives, natives, mildly successful marginal weeds of agriculture, weeds of other settings - accumulate other characteristics which allow them to compete in an environment with a high degree of human management. [ 2 ]


Nonetheless, some of the syndrome traits are themselves phenotypic. [ 2 ]


Some of these are the opposite of  domestication traits . [ 2 ]


Insufficient information is available as to the exact contribution of  mutations , particular  mutation types , pre-existing  genetic diversity , specific genes, and  introgression  to syndrome acquisition. It is also unknown whether we can discern the genetic signatures of adaptation to different weed management regimes from different times.


In some cases domestication alleles may produce weeds that are weedier than the wild parent they were derived from. For example, California wild radish is weedier and more aggressive than  Raphanus raphanistrum , despite being merely a combination of  R. raphanistrum  and  R. raphanistrum' s own subspecies  R. r. sativus .


Pre-existing allelic variety which suddenly became more adaptive when the cultivated environment appeared likely has contributed to the success of  Amaranthus tuberculatus ,  A. palmeri ,  Lolium rigidum  and  Ipomoea purpurea  especially their quick development of herbicide resistance.


On the other hand, novel mutations may be the source herbicide resistance in  Echinochloa crus-galli  and  E. oryzicola , whose worldwide combined populations have developed resistance to nine  modes of action .


Some weeds are themselves the descendants of  crops , while some are unrelated to any cultivated species. [ 3 ]  The origins of those arising from cultivars are variously better and worse understood: Weedy  Helianthus annuus  is well understood as wild/cultivar hybrids, weedy  Secale cereale  and  O. sativa  as purely feral crops,  Beta vulgaris  weeds are highly studied although some further analysis is called for, and at the other end of the spectrum lie  Sorghum halepense [ 2 ]  and weedy races of  S. bicolor , [ 4 ] [ 2 ]  weedy congeners of cultivated  S. bicolor  with complicated interbreeding histories that have yet to be untangled. [ 2 ]  Recently (as of 2020 [update] )  teosintes  have begun invading  Spain  and  France . DNA testing of  Spanish teosinte  shows it to be intermediate between  Zea mays  subsp.  mays  and  Zea mays  subsp.  mexicana . [ 5 ]


Some of these are the same genes as domestication traits, but with alleles of opposite effect. [ 2 ]


Polygonum aviculare ,  Plantago lanceolata ,  Spergularia rubra ,  Senecio vulgaris ,  Poa annua , [ 1 ]  weedy rice,  Sorghum  weeds including  S. halepense [ 2 ]  and weedy races of  S. bicolor , [ 4 ]  weedy  Helianthus annuus . [ 2 ] [ 3 ]


Allelic exclusion  is a process by which only one  allele  of a  gene  is expressed while the other allele is silenced. [ 1 ]  This phenomenon is most notable for playing a role in the development of  B lymphocytes , where allelic exclusion allows for each mature B lymphocyte to express only one type of  immunoglobulin . This subsequently results in each B lymphocyte being able to recognize only one antigen. [ 2 ]  This is significant as the co-expression of both alleles in B lymphocytes is associated with  autoimmunity  and the production of  autoantibodies . [ 3 ]


Many regulatory processes can lead to allelic exclusion. In one instance, one allele of the gene can become transcriptionally silent, resulting in the transcription and expression of only the other allele. [ 2 ]  This could be caused in part by decreased  methylation  of the expressed allele. [ 4 ]  Conversely, allelic exclusion can also be regulated through asynchronous  allelic rearrangement . [ 5 ]  In this case, both alleles are transcribed but only one becomes a functional protein. [ 2 ]


Allelic exclusion has been observed most often in genes for cell surface receptors and has been extensively studied in immune cells such as B lymphocytes. Allelic exclusion of immunoglobulin (Ig) heavy chain and light chain genes in B cells forms the genetic basis for the presence of only a single type of antigen receptor on a given B lymphocyte, which is central in explaining the ‘one B cell — one antibody’ rule. [ 6 ]  The variable domain of the B-cell antigen receptor is encoded by the V, (D), and J gene segments, the recombination of which gives rise to Ig gene allelic exclusion. V(D)J recombination occurs imprecisely, so that while transcripts from both alleles are expressed, only one is able to give rise to a functional surface antigen receptor. If no successful rearrangement occurs on either chromosome, the cell dies.


In the stochastic model, while the Ig rearrangement is proposed to be very efficient, the probability of functional allelic rearrangement is assumed to be very low as compared to the probability of non-functional rearrangement. [ 7 ]  As a result, successful recombination of more than one functional Ig allele in one B cell statistically occurs very infrequently. [ 8 ]


In the asynchronous recombination models, the recombination process is controlled by timing of  recombination-activating gene  (RAG) recombinase and accessibility of each Ig allele within the  chromatin  structure. [ 7 ]


The feedback inhibition model is similar to the asynchronous recombination mode, but it emphasizes the mechanisms that maintain the rearrangement asynchrony. This model suggests that a recombination which gives rise to a functional B cell surface receptor will cause a series of signals which suppress further recombination. [ 10 ]  Without these signals, allelic rearrangement will carry on.  The classic feedback model is empirically corroborated by observed recombination ratios. [ 10 ]


The allelic exclusion of light chain genes Igκ and Igλ is a process that is controlled by the monoallelic initiation of  V(D)J recombination . While little is known about the mechanism leading to the allelic exclusion of Igλ genes, the Igκ locus is generally inactivated by RAG-mediated deletion of the exon Cκ. The V(D)J recombination step is a random and non-specific process that occurs one allele at a time where segments V, (D) and J are rearranged to encode the variable region, resulting in a fraction of functional genes with a productive V(D)J region. [ 11 ]  Allelic exclusion is then enforced via feedback inhibition where the functional Ig gene inhibits V(D)J rearrangement of the second allele. While this feedback mechanism is mainly achieved through inhibition of the juxtaposition of V and D-J segments, the down-regulation of transcription and suppression of RAG accessibility also plays a role. [ 12 ]


Vomeronasal sensory neurons  are found in the  vomeronasal organ  at the  nasal septum  base and their specialty is in  pheromone  detection. [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ] [ 18 ]  A  vomeronasal receptor , V1R, exhibits allelic exclusion. When a V1R receptor  gene  is  expressed , an  odorant receptor  gives  negative feedback  that prevents  transcription  of other V1R receptor genes. [ 13 ] [ 14 ] [ 15 ] [ 16 ]  In mice vomeronasal sensory neurons, an odorant receptor  coding sequence 's  exogenous  transcription from a V1R  promoter  can stop  endogenous  V1R genes from being transcribed. [ 13 ] [ 14 ] [ 15 ] [ 16 ]  They [ 13 ]  also obtained data supporting  monoallelic expression  of  V1rb2 mv  and  V1rb2 vg  alleles and monogenic expression of the  V1rb2  locus. [ 13 ]


Monoallelic expression was also found in  mice   olfactory receptor  genes in  olfactory sensory neurons . [ 14 ] [ 15 ] [ 16 ]  An  upstream   cis-acting   DNA  region controls an olfactory receptor gene cluster's activation and resulted in monogenic expression of one olfactory receptor gene. [ 14 ] [ 15 ] [ 16 ]  The expressed coding region's disruption or deletion resulted in expression of a second olfactory receptor gene. [ 15 ]  Based on this, they [ 15 ]  hypothesized that in order to enforce the "one receptor-one neuron rule” (Serizawa et al, 2003 [ 15 ] ), one olfactory receptor gene's  random  activation and the expressed gene product's  negative feedback  are necessary. [ 14 ] [ 15 ] [ 16 ]


Intracellular  GATA3  expression is a crucial component of  T cell receptor  beta (TCR𝛽) allelic exclusion in  mammalian   cells . [ 14 ] [ 15 ] [ 16 ] [ 19 ] [ 20 ]  GATA3  transgenic  overexpression by a 2.5- to 5-fold increase partly due to  Gata3  transcriptional activation from  monoallelic  to biallelic primarily resulted in both  alleles  of TCR𝛽  recombining . [ 14 ]  Intracellular GATA3 expression can divide  wild-type  immature  thymocyte  cell populations. [ 14 ] [ 15 ] [ 16 ] [ 19 ] [ 20 ]  Although cells regardless of GATA3 expression level yielded functional TCR𝛽 sequences, there was nearly sole recombination of one  Tcrb  locus in lowly expressed GATA3 cells and constant recombination of both alleles in highly expressed GATA3 cells. [ 14 ]


V𝛽  Recombination signal sequences  (RSSs) with poor qualities suppressed one allele's expression of two TCR𝛽 genes. [ 21 ] [ 22 ]  These poor quality V𝛽 RSSs decreased the chances of upstream V𝛽 and V31 recombination on the same allele, which in turn enabled functional TCR𝛽 genes’ monoallelic assembly and expression. [ 21 ] [ 22 ]  However, poor quality V𝛽 RSSs were unlikely to result in monogenic TCR𝛽 expression alone and might have involved other  epigenetic  processes. [ 21 ] [ 22 ]  RSSs is involved in mammalian TCR𝛽 genes’ monogenic assembly and expression and may also be involved in other mammalian TCR-related genes. [ 21 ]  Low quality V𝛽  recombinase  targets randomly constrain two functional rearrangements’ production which imposes TCR𝛽 allelic exclusion. [ 22 ]


The word  allotype  comes from two Greek roots,  allo  meaning 'other or differing from the norm' and  typos  meaning 'mark'. [ 1 ]  In  immunology , allotype is an  immunoglobulin  variation (in addition to  isotypic  variation) that can be found among  antibody classes  and is manifested by heterogeneity of  immunoglobulins  present in a single  vertebrate  species. The structure of  immunoglobulin polypeptide chain  is dictated and controlled by number of genes encoded in the  germ line . [ 2 ]  However, these  genes , as it was discovered by serologic and chemical methods, could be highly  polymorphic . This  polymorphism  is subsequently projected to the overall  amino acid  structure of  antibody chains .  Polymorphic   epitopes  can be present on  immunoglobulin constant regions  on both heavy and light chains, differing between individuals or ethnic groups and in some cases may pose as  immunogenic determinants . [ 3 ]  Exposure of individuals to a non-self allotype might elicit an anti- allotype response and became cause of problems for example in a patient after transfusion of blood [ 4 ]  or in a pregnant woman. [ 5 ]  However, it is important to mention that not all variations in  immunoglobulin  amino acid sequence pose as a determinant responsible for immune response. Some of these allotypic determinants may be present at places that are not well exposed and therefore can be hardly serologically discriminated. In other cases, variation in one isotype can be compensated by the presence of this determinant on another antibody  isotype  in one individual. [ 6 ]  This means that divergent allotype of heavy chain of IgG  antibody  may be balanced by presence of this allotype on heavy chain of for example IgA  antibody  and therefore is called isoallotypic variant. Especially large number of  polymorphisms  were discovered in IgG  antibody  subclasses. Which were practically used in forensic medicine and in paternity testing, before replaced by modern day  DNA fingerprinting . [ 4 ]


Human allotypes nomenclature was first described in alphabetical system and further systematized in numerical system, but both could be found in the literature. [ 7 ] [ 8 ]  For example, allotype expressed on constant region of heavy chain on IgG are designated by Gm which stands for ‘genetic marker ‘ together with IgG subclass (IgG1 àG1m, IgG2 àG2m) and the allotype number or letter [ G1m1/ G1m (a) ].  Polymorphisms  within IgA are denoted in the same way as A2m (eg. A2m1/2) and kappa light chains constant region  polymorphisms  as Km (eg. Km1). Despite the fact, that there are multiple known lambda chain  isotypes , there have not been reported any lambda chain serological  polymorphisms . [ 9 ]


All these before mentioned allotypes are expressed on constant regions of the  immunoglobulin .  Genes  responsible for encoding structure of constant regions of heavy chains are closely linked and therefore inherited together as one  haplotype  with low number of  crossovers . Although some  crossovers  did occur during  human evolution  resulting in the creation of current populations characteristic  haplotypes  and importance of allotype system in population studies. [ 10 ] , [ 11 ]