McLeod syndrome is very rare. There are approximately 150 cases of McLeod syndrome worldwide. Because of its X-linked mode of inheritance, it is much more prevalent in males. [ 10 ]


Many other neurological conditions are associated with acanthocytosis but are not considered 'core' acanthocytosis syndromes. The commonest are:


Currently, no treatment slows the  neurodegeneration  in any of the neuroacanthocytosis disorders. Medication may be administered to decrease the involuntary movements produced by these syndromes.  Antipsychotics  are used to block  dopamine ,  anticonvulsants  treat seizures and  botulinum toxin  injections may control dystonia. Patients usually receive  speech ,  occupational  and  physical  therapies to help with the complications associated with movement.  Sometimes, physicians will prescribe  antidepressants  for the psychological problems that accompany neuroacanthocytosis. [ 5 ]  Some success has been reported with  deep brain stimulation . [ 11 ] [ 12 ]


Mouthguards and other physical protective devices may be useful in preventing damage to the lips and tongue due to the orofacial chorea and dystonia typical of chorea acanthocytosis. [ 2 ]


Neuroacanthocytosis was first identified in 1950 as  Bassen-Kornzweig disease , or Bassen-Kornzweig Syndrome, a rare, autosomal recessive, childhood-onset disorder in which the body fails to produce  chylomicrons , low density  lipoprotein  (LDL) and very low density lipoprotein (VLDL). Symptoms include  ataxia ,  peripheral neuropathy ,  retinitis pigmentosa  and other forms of nerve dysfunction. It was first noted by the North American  physician   Frank Bassen , who later partnered with the ophthalmologist  Abraham Kornzweig  to identify and describe causes and symptoms of the disease. Affected children appear normal at birth but usually fail to thrive during their first year. [ 13 ] [ 14 ]


A second form of neuroacanthocytosis, Levine-Critchley syndrome, was discovered by the American internist  Irvine M. Levine  in 1960 and reported in  Neurology  in 1964, and again in 1968. [ 15 ]  Subsequently, similar symptoms were identified and described by the British neurologist  MacDonald Critchley  in 1968. [ 16 ]  In both cases, the physicians described a hereditary syndrome that combined acanthocytosis with neurological peculiarities but normal serum lipoprotein. Specific symptoms included tics, grimacing, movement disorders, difficulty swallowing, poor coordination,  hyporeflexia , chorea, and seizures. Patients often mutilated their tongues, lips, and cheeks. The diseases appeared in both sexes, and were usually diagnosed in infancy. [ 17 ]


Research is underway worldwide to increase scientific understanding of these disorders as well to identify prevention and treatment methods.  Known genetic mutations provide a basis for studying some of the conditions. [ 5 ]


Chromosome+disorders  at the U.S. National Library of Medicine  Medical Subject Headings  (MeSH)


NM_145912 NM_001318323 NM_001371362


NM_001271411 NM_001271412 NM_001271413 NM_001271414 NM_028728


NP_001305252 NP_666017 NP_001358291


NP_001258340 NP_001258341 NP_001258342 NP_001258343 NP_083004


NFAT activating protein with ITAM motif 1  is a  protein  that in humans is encoded by the NFAM1  gene .
 [ 5 ]


The protein encoded by this gene is a type I membrane receptor that activates cytokine gene promoters such as the IL-13 and TNF-alpha promoters. The encoded protein contains an immunoreceptor tyrosine-based activation motif (ITAM) and is thought to regulate the signaling and development of B-cells. [provided by RefSeq, Jul 2008].


OSER1 (Oxidative Stress Responsive Serine Rich 1) , or  Chromosome 20  open reading frame  111 ,  C20orf111 , is the hypothetical  protein  that in humans is encoded by the  OSER1   gene . [ 5 ]  OSER1/C20orf111 is also known as  Perit1  (peroxide inducible transcript 1),  HSPC207 , and  dJ1183I21.1 . [ 6 ]  It was originally located using genomic sequencing of chromosome 20. [ 7 ]   The National Center for Biotechnology Information, or  NCBI , [ 5 ]  shows that it is located at q13.11 on chromosome 20, however the genome browser at the University of California-Santa Cruz (UCSC) website [ 8 ]  shows that it is at location q13.12, and within a million base pairs of the  adenosine deaminase  locus. [ 9 ]  It was also found to have an increase in expression in cells undergoing hydrogen peroxide( H 2 O 2 )-induced apoptosis. [ 10 ]  After analyzing the amino acid content of OSER1, it was found to be rich in serine residues.


OSER1  a valid, protein coding gene that is found on the minus strand of  chromosome 20  at q13.12 by searching the UCSC Genome Browser, [ 8 ]  but q13.11 according to Refseq on NCBI. [ 5 ]


A few of the known genes near  OSER1  are given in the box below with their known function.


10 splice isoforms that encode good proteins, altogether 8 different isoforms, 2 of which are complete isoforms. The image below shows the 10 isoforms that are predicted. [ 15 ]  Of these 10 splice isoforms, 8 have varying  peptide  lengths, however all of these proteins are only hypothetical with no extensive research done on them. [ 15 ]


When looking at the predicted promoter sequence, [ 16 ]  there are no  RNA Polymerase II  binding sites, however there is a binding site for core promoter element for TATA-less promoters. [ 17 ]  In this same region of the promoter, there is also a TATA-binding factor sequence, which helps in the positioning of RNA polymerase II for transcription. [ 18 ]


The function of OSER1 is not well understood by the scientific community in general. It does contain a domain of unknown function, DUF776, which has a large segment that is well conserved from  Caenorhabditis elegans  to humans. [ 21 ]  Its expression is increased in rat  cardiomyocytes  undergoing  hydrogen peroxide  induced  apoptosis . [ 10 ]  It has also been shown that its overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan. [ 21 ]  This effect might be due to its regulation of mitochondrial biology and oxidative stress. [ 21 ]  Moreover, it promotes reproduction in animal models and is associated with human reproduction and longevity. [ 21 ]


When looking at the EST Profiles in humans, normal tissue (non-cancerous), expresses at a level of 82 transcripts per million. [ 22 ]  OSER1 has been shown to increase in expression in rat cardiac myocytes undergoing |H|2|O|2|-induced apoptosis, suggesting a role in cell death. [ 10 ]  In bladder, cervical, head and neck, non-neoplasia, pancreatic, and prostate cancer cells, there are expression levels lower than normal. [ citation needed ]


OSER1 gene has no clear  paralogs  in the human  genome . However, it has many  orthologs  in other organisms, and is conserved highly in organisms such as  Xenopus tropicalis  and is semi-conserved in the proto-animal  Trichoplax adherens  at the  C-terminus .


The following table presents a select number of the orthologs found. [ 23 ]


The image below is a  multiple sequence alignment  comparing the conservation of the OSER1 protein amongst other organisms. The protein is highly conserved in the DUF776 region amongst vertebrates, and also at the  C-terminus  in eukaryotes.


Using tools at ExPASy [ 24 ]  the following are predicted  post-translational modifications  for OSER1.


PELE (Protein Secondary Structure Prediction) was used to predict the secondary structure of OSER1. There is little in the way of  β-strand  or  α-helix  secondary structure, but a large part of the protein appears to exist as random coils. This is shown on the image of the OSER1 images to the right.


In  genetics , a  polycentric chromosome  is any  chromosome  featuring multiple  centromeres . [ 1 ]  Polycentric chromosomes are produced by chromosomal aberrations such as deletion, duplication, or  translocation . [ citation needed ]  Polycentric chromosomes usually result in the death of the cell because polycentric chromosomes may fail to move to opposite poles of  spindle fiber  during  anaphase . As a result, the chromosome is fragmented, which causes the  death of the cell . In some  algae , such as  Spirogyra , polycentric chromosomes appear normally. [ 2 ]  They also occur in the sedge,  Luzula . [ 3 ]


Polytene chromosomes  are large  chromosomes  which have thousands of  DNA  strands. They provide a high level of function in certain tissues such as  salivary glands  of insects. [ 1 ]


Polytene chromosomes were first reported by  E.G.Balbiani  in 1881. Polytene chromosomes are found in  dipteran flies : the best understood are those of  Drosophila ,  Chironomus  and  Rhynchosciara . They are present in another group of arthropods of the class  Collembola , a protozoan group  Ciliophora , mammalian  trophoblasts  and  antipodal , and suspensor cells in plants. [ 2 ]  In insects, they are commonly found in the  salivary glands  when the cells are not dividing.


They are produced when repeated rounds of  DNA replication  without  cell division  forms a giant chromosome. Thus polytene chromosomes form when multiple rounds of replication produce many sister  chromatids   which stay fused together .


Polytene chromosomes, at  interphase , are seen to have distinct thick and thin banding patterns. These patterns were originally used to help map chromosomes, identify small  chromosome mutations , and in  taxonomic  identification. They are now used to study the function of genes in  transcription . [ 3 ]


In addition to increasing the volume of the cells' nuclei and causing cell expansion, polytene cells may also have a metabolic advantage as multiple copies of genes permits a high level of  gene expression . In  Drosophila melanogaster , for example, the chromosomes of the larval salivary glands undergo many rounds of  endoreduplication  to produce large quantities of adhesive  mucoprotein  ("glue") before  pupation .  Another example within the fly itself is the tandem duplication of various polytene bands located near the  centromere  of the  X chromosome  which results in the Bar phenotype of kidney-shaped eyes. [ 4 ] [ 5 ]


The interbands are involved in the interaction with the active chromatin proteins,  nucleosome  remodeling, and  origin recognition complexes . Their primary functions are: to act as binding sites for  RNA pol II , to initiate replication and, to start nucleosome remodeling of short fragments of DNA. [ 6 ]


In insects, polytene chromosomes are commonly found in the salivary glands; they are also referred to as "salivary gland chromosomes". The large size of the chromosome is due to the presence of many longitudinal strands called  chromonemata ; hence the name polytene (many stranded). They are about 0.5 mm in length and 20 μm in diameter. The chromosomal strands are formed after repeated division of the chromosome in the absence of cytoplasmic division. This type of division is called  endomitosis . The polytene chromosome contains two types of bands, dark bands and interbands. The dark bands are darkly stained and the inter bands are lightly stained with nuclear stains. The dark bands contain more DNA and less RNA. The interbands contain more RNA and less DNA. The amount of DNA in interbands ranges from 0.8 - 25%. [ 2 ]


The bands of polytene chromosomes become enlarged at certain times to form swellings called puffs. The formation of puffs is called puffing. In the regions of puffs, the chromonemata uncoil and open out to form many loops. The puffing is caused by the uncoiling of individual chromomeres in a band. The puffs indicate the site of active genes where mRNA synthesis takes place. [ 7 ]  The chromonemata of puffs give out a series of many loops laterally. As these loops appear as rings, they are called Balbiani rings after the name of the researcher who discovered them. They are formed of DNA, RNA and a few proteins. As they are the site of transcription, transcription mechanisms such as  RNA polymerase  and  ribonucleoproteins  are present.


In protozoans, there is no transcription, since the puff consists only of DNA. [ 2 ]


Polytene chromosomes were originally observed in the larval  salivary glands  of  Chironomus  midges by  Édouard-Gérard Balbiani  in 1881. [ 8 ]  Balbiani described the chromosomal puffs among the tangled thread inside the nucleus, and named it "permanent spireme". In 1890, he observed similar spireme in a ciliated protozoan  Loxophyllum meleagris . [ 1 ]  The existence of such spireme in  Drosophila melanogaster  was reported by Bulgarian geneticist Dontcho Kostoff in 1930. Kostoff predicted that the discs (bands) which he observed were "the actual packets in which inherited characters are passed from generation to generation." [ 9 ]


The hereditary nature of these structures was not confirmed until they were studied in  Drosophila melanogaster  in the early 1930s by German biologists  Emil Heitz  and Hans Bauer. In 1930, Heitz studied different species of  Drosophila  ( D. melanogaster ,  D. simulans ,  D. hydei , and  D. virilis ) and found that all their interphase chromatins in certain cells were swollen and messy. In 1932, he collaborated with Karl Heinrich Bauer with whom he discovered that the tangled chromosomes having distinct bands are unique to the cells of the salivary glands, midgut, Malphigian tubules, and brain of the flies  Bibio hurtulunus  and  Drosophila funebris . The two papers were published in the early 1933. [ 10 ]  Unaware of these papers, an American geneticist  Theophilus Shickel Painter  reported in December 1933 the existence of giant chromosome in  D. melanogaster  (followed by a series of papers the following year). [ 11 ] [ 12 ]  Learning of this, Heitz accused Painter of deliberately ignoring their original publication to claim priority of discovery. [ 13 ]  In 1935,  Hermann J. Muller  and A.A. Prokofyeva established that the individual band or part of a band corresponds with a gene in  Drosophila . [ 14 ]  The same year, P.C. Koller hesitantly introduced the name "polytene" to describe the giant chromosome, writing:


It seems that we can regard these chromosomes as corresponding with paired pachytene chromosomes at meiosis in which the intercalary parts between chromomeres have been stretched and separated into smaller units, and in which, instead of two threads lying side by side, we have 16 or even more. Hence they are "polytene" rather than pachytene; I do not, however, propose to use this term; I shall refer to them as "multiple threads." [ 15 ]


Polytene chromosomes are present in secretory tissues of  dipteran  insects such as the  Malpighian tubules  of  Sciara  and also in  protists ,  plants ,  mammals , or in cells from other  insects . Some of the largest polytene chromosomes described thus far occur in larval salivary gland cells of the  chironomid  genus  Axarus .


In plants, they are found in only a few species, and are restricted to ovary and immature seed tissues such as in  Phaseolus coccineus  and  P. vulgaris  (Nagl, 1981), and the anther tapetum of  Vigna unguiculata   and of some  Phaseolus  species. [ 16 ]


Polytene chromosomes are also used to identify the species of chironomid larvae that are notoriously difficult to identify. Each morphologically distinct group of larvae consists of a number of morphologically identical (sibling) species that can only be identified by rearing adult males or by cytogenetic analysis of the polytene chromosomes of the larvae. Karyotypes are used to confirm the presence of specific species and to study genetic diversity in species with a wide range of genetic variation. [ 17 ] [ 18 ]


Premature chromosome condensation  ( PCC ), also known as  premature mitosis , occurs in  eukaryotic  organisms when  mitotic   cells  fuse with  interphase  cells. [ 1 ]   Chromatin , a substance that contains genetic material such as  DNA , is normally found in a loose bundle inside a cell's nucleus. During the  prophase  of mitosis, the chromatin in a cell compacts to form condensed  chromosomes ; this condensation is required in order for the cell to divide properly. While mitotic cells have condensed chromosomes, interphase cells do not. PCC results when an interphase cell fuses with a mitotic cell, causing the interphase cell to produce condensed chromosomes prematurely.


The appearance of a prematurely condensed chromosome depends on the stage that the interphase cell was in. [ 1 ]  Chromosomes that are condensed during the  G 1  phase  are usually long and have a single strand, while chromosomes condensed during the  S phase  appear crushed. Condensation during the  G 2  phase  yields long chromosomes with two  chromatids .


PCC was first reported in 1968, of viral-infected cells showing strange appearance of chromosomes. It was found that the strange appearance was selectively observed in S-phase nuclei, and therefore concluded that the nuclei of cells fused in mitotic cells condensed prematurely by unknown material which accumulated in mitotic cells, and observed chromosome structures that are equivalent to those in  cell fusion . This material was named as the  mitosis promoting factor  (MPF).


The precise mechanism of chromosome condensation, as well as the premature condensation, is still in question. It is only known that MPF is a key enzyme that induces PCC in  somatic cells  or  oocytes , as they play a key role in cell cycle regulation and cell growth control. When the interphase nuclei is exposed to activated MPF, which is supplied from the mitotic nuclei, PCC is induced. [ 2 ]


Radiation hybrid mapping  (also known as  RH mapping ) is a technique for  mapping  mammalian  chromosomes . [ 1 ]


Radiation hybrid mapping consists of several steps. A  radiation hybrid  is "a cell or organism that contains fragments of chromosomes from a second organism". [ 2 ] : 82   Radiation hybrids are generated by using  X-rays  to randomly break chromosomes into fragments, then implanting the fragments into non-irradiated rodent cells, which replicate and thus clone the chromosomes.


Then these clones are analyzed for the presence of certain  DNA markers . If two given DNA markers are far apart on the initial chromosome, then it is likely that they will appear in distinct fragments. The frequency of the separation of the markers into different fragments is used to estimate the chromosomal distance between them. RH mapping has lower resolution than  optical mapping , but is still of high enough resolution to be valuable. For example, the RH procedure was used to map 14 DNA probes from a region of human chromosome 21 spanning 20 megabase pairs. [ 3 ]  Radiation hybrid mapping was also used in constructing early physical maps of the human genome. [ 2 ]


The  Escherichia coli   chromosome  shows two main levels of global organization,  macrodomains  and replichores. [ 1 ]  In E. coli chromosomes, the origin and terminus of replication divide the genome into oppositely replicated halves called replichores. Replichore 1, which is replicated clockwise, has the presented strand of E. coli as its leading strand; in replichore 2 the complementary strand is the leading one. Many features of E. coli are oriented with respect to replication. [ 2 ]


Ring chromosome 22 , also known as  ring 22 , is a rare  chromosomal disorder .  Ring chromosomes  occur when the ends of a chromosome  lose material  and fuse into a ring shape; in the case of ring 22, this occurs for  chromosome 22 , the last numbered human  autosome . Ring chromosome 22 is marked by a number of consistent  traits , such as  intellectual disability , speech delay,  hypotonia , and hyperactivity. The condition has a similar  phenotype  to  Phelan-McDermid syndrome , as the loss of the  SHANK3  gene is implicated in both.


Though ring chromosome 22 has a variable phenotype, a number of consistent features between most cases have been noticed. Most cases have  intellectual disability , generally in the moderate to profound range. Other prevalent features include  hypotonia  (unusual weakness or floppiness of the skeletal muscles), significant hyperactivity, and autism-like features. [ 1 ]  Significant speech delay is common; in a sample of 35 cases with a median age of 10, over half of the participants were unable to speak, and those who did spoke their first words on average at nearly three years of age. [ 2 ]  Poor coordination and an unsteady  gait  are also frequent findings. A number of  craniofacial  anomalies are common, such as  microcephaly ,  epicanthic folds , and unusually large ears. [ 3 ]  Other common facial features include almond-shaped eyes with long lashes, [ 1 ]  thick eyebrows, [ 4 ]  a bulbous nose, and a " sandal gap " between the toes. [ 2 ]  Height is usually normal, and physical abnormalities in general mild or absent. [ 1 ]


Genitourinary  and reproductive abnormalities have been reported. A case is known of an otherwise phenotypically normal man with a ring 22 and  azoospermia , [ 5 ]  and one symptomatic case has been reported of a girl with a malformed clitoris. [ 2 ]  Though most cases are accompanied by significant disability, reports have been made of intergenerational transmission with some mild or  asymptomatic  cases. A family has been reported where the ring chromosome 22 was passed down through three generations, with some members demonstrating the traditional symptoms and some not. [ 6 ]


Hyperactive behaviour is frequently reported. [ 7 ]   Bipolar disorder  has been reported in adults with ring chromosome 22, and a link between hyperactivity and atypical bipolar disorder  speculated. [ 8 ]  Autistic-like traits are common in young children, although often abate by  preadolescence . [ 1 ]  Relatively few ring 22 patients fit the full criteria for autism, and it is unclear if such an association genuinely exists or is a consequence of the correlation between autism and developmental delay in general. [ 9 ]


Neurofibromatosis type II  occurs in a significant minority of cases of ring chromosome 22. The presence of multiple  meningiomas  is particularly common. [ 10 ]


Ring chromosome 22 is caused by a  ring chromosome , a form of  chromosome mutation  where the ends of a chromosome lose genetic material and attach to one another, forming a ring. Chromosome 22 is one of the  acrocentric chromosomes , meaning the  short arm  is unusually small and lacks genes relevant to development; accordingly, the phenotype of ring chromosome 22 is caused only by the loss of genes in the long arm. [ 1 ]  The amount of genes lost in a  deletion  can vary significantly, with reports of the loss of anywhere between 0.15% and 21% of chromosome 22 in different symptomatic cases. [ 2 ]


Ring chromosomes virtually always arise sporadically, with few documented cases of parent-to-child transmission. Due to the inherent instability of ring chromosomes, inheritance is uncommon even with affected parents. [ 11 ]  However, cases have been reported of intergenerational inheritance of ring chromosome 22. [ 6 ]


Significant overlap exists between the phenotype of ring chromosome 22 and that of  Phelan-McDermid syndrome , another chromosome 22 deletion syndrome. This is ascribed to a shared deletion of the  SHANK3  gene at  22q13.3 . Reports exist of people with ring 22 who lack the  SHANK3  deletion and have normal phenotypes, marking  SHANK3  as a critical region for the ring chromosome 22 syndrome. [ 11 ]


Ring chromosome 22, like other major chromosomal disorders, is diagnosed via  karyotype . Rarely, it may be detected prenatally by  amniocentesis  or  chorionic villus sampling . [ 3 ]


As the underlying ring chromosome is an innate genetic disorder, it cannot by itself be treated. Rather, treatment is symptomatic and supportive.  Special education  is generally indicated due to intellectual disability, while  speech therapy  may partially overcome speech delays.  Physical therapy  can assist with hypotonia.  Genetic counselling  is broadly indicated for potentially heritable genetic disorders. [ 3 ]


Ring chromosome 22 is rare, with around 100 cases reported. [ 7 ]  It may be more common in females than males, [ 3 ]  although other researchers have found the opposite. [ 12 ]


Ring chromosomes  21  and 22 were first identified in 1970. At the time, the two chromosomes could not be differentiated by contemporary  cytogenetic  analysis and were both referred to as the "G chromosome", with ring chromosome 22 being referred to as "G-deletion syndrome II"; as techniques advanced, G-deletion syndrome II was identified as ring chromosome 22. [ 13 ]  Early reports were split on the topic of whether ring chromosome 22 constituted a consistent syndrome or simply a finding in a heterogeneous group of intellectually disabled people. [ 14 ]  One early case that drew attention to the syndrome was a report of  monozygotic twin  sisters with a ring 22, one of the first recorded reports of a shared chromosomal anomaly between twins. [ 15 ]


Satellite chromosomes  or  SAT-chromosomes  are  chromosomes  that contain secondary constructs that serve as identification. They are observed in  acrocentric chromosomes.  In addition to the  centromere , one or more  secondary constrictions  can be observed in some chromosomes at  metaphase . In humans they are usually associated with the short arm of an  acrocentric  chromosome, [ 1 ]  such as in the chromosomes 13, 14, 15, 21, & 22. [ 2 ] [ 3 ]  The  Y chromosome  can also contain satellites, although these are thought to be translocations from autosomes. [ 4 ]  The secondary constriction always keeps its position, so it can be used as markers to identify specific chromosomes.


The name derives from the small chromosomal segment behind the  secondary constriction , called a  satellite , named by  Sergei Navashin , in 1912. [ 5 ]  Later, Heitz (1931) qualified the secondary constriction as the SAT state ( Sine Acido Thymonucleinico , which means "without thymonucleic acid"), because it didn't stain with the  Feulgen reaction . With time, the term "SAT-chromosome" became an abbreviation for satellite chromosome. [ 6 ] [ 7 ] [ 8 ]


The satellite at metaphase appears to be attached to the  chromosomes  by a thread of  chromatin .


SAT-chromosomes whose secondary constriction is associated with the formation of the  nucleolus  are referred to as nucleolar SAT-chromosomes. There are at least 4 SAT-chromosomes in each diploid nucleus, and the constriction corresponds to a  nucleolar organizer  (NOR), a region containing multiple copies of the  18S  and  28S   ribosomal genes  that synthesize  ribosomal RNA  required by  ribosomes . The appearance of secondary constrictions at NORs is thought to be due to  rRNA   transcription  and/or structural features of the  nucleolus  impeding chromosome  condensation . [ 9 ]


Sex chromosomes  (also referred to as  allosomes ,  heterotypical chromosome, gonosomes ,  heterochromosomes , [ 1 ] [ 2 ]  or  idiochromosomes [ 1 ] ) are  chromosomes  that
carry the genes that determine the sex of an individual. The human sex chromosomes are a typical pair of  mammal  allosomes. They differ from  autosomes  in form, size, and behavior. Whereas autosomes occur in homologous pairs whose members have the same form in a  diploid cell , members of an allosome pair may differ from one another.


Nettie Stevens  and  Edmund Beecher Wilson  both independently discovered sex chromosomes in 1905. However, Stevens is credited for discovering them earlier than Wilson. [ 3 ]


In humans, each  cell nucleus  contains 23 pairs of chromosomes, a total of 46 chromosomes. The first 22 pairs are called  autosomes . Autosomes are  homologous chromosomes  i.e. chromosomes which contain the same  genes  (regions of DNA) in the same order along their chromosomal arms. The 23rd pair of chromosomes are called allosomes. These consist of two  X chromosomes  in females, and an X chromosome and a  Y chromosome  in males. Females therefore have 23 homologous chromosome pairs, while males have 22. The X and Y chromosomes have small regions of homology called  pseudoautosomal regions .


An X chromosome is always present as the 23rd chromosome in the  ovum , while either an X or Y chromosome may be present in an individual  sperm . [ 4 ]  Early in female embryonic development, in cells other than egg cells, one of the X chromosomes is randomly and permanently partially  deactivated : In some cells, the X chromosome inherited from the mother deactivates; in other cells, it is the X chromosome inherited from the father. This ensures that both sexes always have exactly one functional copy of an X chromosome in each body cell. The deactivated X chromosome is silenced by repressive  heterochromatin  that compacts the DNA and prevents expression of most genes. This compaction is regulated by  PRC2  (Polycomb Repressive Complex 2). [ 5 ]


All  diploid  organisms with allosome-determined sex get half of their allosomes from each of their parents. In most mammals, females are XX, and can pass along either of their Xs; since males are XY they can pass along either an X or a Y. Females in such species receive an X chromosome from each parent while males receive an X chromosome from their mother and a Y chromosome from their father. It is thus the male's sperm that determines the sex of each offspring in such species.


However, a small percentage of humans have a divergent sexual development, known as  intersex .  This can result from allosomes that are neither XX nor XY.  It can also occur when two fertilized embryo fuse, producing a  chimera  that might contain two different sets of DNA one XX and the other XY. [ citation needed ]   It could also result from exposure, often in utero, to chemicals that disrupt the normal conversion of the allosomes into sex hormones and further into the development of either  ambiguous outer genitalia or internal organs . [ 6 ]


There is a gene in the Y chromosome that has regulatory sequences that control genes that code for maleness, called the  SRY gene . [ 7 ]  This gene produces a testis-determining factor ("TDF"), which initiates testis development in humans and other mammals. The SRY sequence's prominence in sex determination was discovered when the genetics of  sex-reversed XX men  (i.e. humans who possess biological male-traits but actually have XX allosomes) were studied. After examination, it was discovered that the difference between a typical XX individual (traditional female) and a sex-reversed XX man was that the typical individuals lacked the SRY gene. It is theorized that in sex-reversed XX men, the SRY gets  translocated  to an X chromosome in the XX pair during  meiosis . [ 8 ]


Diverse mechanisms are involved in the determination of sex in animals. [ 9 ]  For mammals, sex determination is carried by the genetic contribution of the spermatozoon.  Many lower chordates, such as fish, amphibians and reptiles, have systems that are influenced by the environment. Fish and amphibians, for example, have genetic sex determination but their sex can also be influenced by externally available steroids and incubation temperature of eggs. [ 10 ] [ 11 ]  In some reptiles, e.g.  sea turtles , only the incubation temperature determines sex ( temperature-dependent sex determination ).


Many scientists argue that sex determination in plants is more complex than that in humans. This is because even  flowering plants  have a variety of mating systems, their sex determination  primarily regulated by MADS-box genes. These genes code for proteins that form the sex organs in flowers. [ 12 ]


Plant sex chromosomes are most common in  bryophytes , relatively common in  vascular plants  and unknown in  ferns  and  lycophytes . [ 13 ]  The diversity of plants is reflected in their sex-determination systems, which include XY and  UV  systems as well as many variants. Sex chromosomes have evolved independently across many plant groups. Recombination of chromosomes may lead to  heterogamety  before the development of sex chromosomes, or recombination may be reduced after sex chromosomes develop. [ 14 ]  Only a few  pseudoautosomal regions  normally remain once sex chromosomes are fully differentiated. When chromosomes do not recombine, neutral sequence divergences begin to accumulate, which has been used to estimate the age of sex chromosomes in various plant lineages. Even the oldest estimated divergence, in the liverwort  Marchantia polymorpha ,  is more recent than mammal or bird divergence. Due to this recency, most plant sex chromosomes also have relatively small sex-linked regions. Current evidence does not support the existence of plant sex chromosomes more ancient than those of  M. polymorpha . [ 15 ]


The high prevalence of  autopolyploidy  in plants also impacts the structure of their sex chromosomes. Polyploidization can occur before and after the development of sex chromosomes. If it occurs after sex chromosomes are established, dosage should stay consistent between the sex chromosomes and autosomes, with minimal impact on sex differentiation. If it occurs before sex chromosomes become heteromorphic, as is likely in the octoploid red sorrel  Rumex acetosella , sex is determined in a single XY system. In a more complicated system, the sandalwood species  Viscum fischeri  has X1X1X2X2 chromosomes in females, and X1X2Y chromosomes in males. [ 16 ]


Amplification of transposable elements,  tandom repeats  especially accumulation of long tandom repeats ( LTR )  retrotransposones  are responsible for plant sex chromosome evolution. The insertion of retrotransposons is probably the major cause of y-chromosome expansion and  plant genome  size evolution. Retrotransposones contribute in size determination of sex chromosomes and its proliferation varies even in closely related species.  LTR and tandom repeats play dominant role in the evolution of  S. latifolia  sex chromosomes. [ 17 ]  Athila is new family of retroelements, discovered in  Arabidopsis thaliana , present in  heterochromatin  region only.  Athila retroelements overrepresented in X but absent in Y while tandem repeats enriched in Y-chromosome. Some  chloroplast  sequences have also been identified in the Y-chromosome of  S. latifolia .  S. vulgaris  has more retroelements in their sex chromosomes compare to  S. latifolia .  Microsatellite  data shows that there is no significant difference between X and Y-chromosome microsatellites in both  Silene  species. This would conclude that microsatellites do not participate in Y-chromosome evolution. The portion of Y-chromosome that never recombine with X-chromosome faces selection reduction. This reduced selection leads to insertion of transposable elements and accumulation of  deleterious mutation . The Y become larger and smaller than X due to insertion of retroelement and deletion of genetic material respectively. The genus  Humulus  is also used as model for the study of sex chromosomes evolution. Based on the  phylogenetic  topology distribution there are three regions on sex chromosomes. One region that stops recombining in the  ancestor  of  H. lupulus , second that stops recombining in modern  H. lupulus  and the third region called pseudoautosomal region.  H. lupulus  is the rare case in plants in which Y is smaller than X, while its ancestor plant has the same size of both X and Y chromosomes. This size difference should be caused by deletion of  genetic material  in Y but that is not the case. This is because of complex dynamics like the larger size of X than Y-chromosome may be due to  duplication  or retrotransposition and size of Y remains same. [ 18 ]


Ferns and lycophytes have bisexual  gametophytes , so there is no evidence for sex chromosomes. [ 13 ]  In the bryophytes, including liverworts, hornworts and mosses, sex chromosomes are common. The sex chromosomes in bryophytes affect what type of gamete is produced by the gametophyte, and there is wide diversity in gametophyte type. Unlike seed plants, where gametophytes are always unisexual, in bryophytes they may produce male, female, or both types of gamete. [ 19 ]


Bryophytes most commonly employ a UV sex-determination system, where U produces female gametophytes and V produces male gametophytes. The U and V chromosomes are heteromorphic with U larger than V and are frequently both larger than the autosomes. There is variation even within this system, including UU/V and U/VV chromosome arrangements. In some bryophytes,  microchromosomes  have been found to co-occur with sex chromosomes and likely impact sex determination. [ 19 ]


Dioecy is common among  gymnosperms , found in an estimated 36% of species. However, heteromorphic sex chromosomes are relatively rare, with only five species known as of 2014. Five of these use an XY system, and one ( Ginkgo biloba ) uses a WZ system. Some gymnosperms, such as Johann's Pine ( Pinus johannis ), have homomorphic sex chromosomes that are almost indistinguishable through  karyotyping . [ 16 ]


Cosexual  angiosperms  with either monoecious or hermaphroditic flowers do not have sex chromosomes. Angiosperms with separate sexes (dioecious) may use sex chromosomes or environmental flowers for sex determination.  Cytogenetic  data from about 100 angiosperm species showed heteromorphic sex chromosomes in approximately half, mostly taking the form of XY sex-determination systems. Their Y is typically larger, unlike in humans; however there is diversity among angiosperms. In the Poplar genus ( Populus ) some species have male heterogamety while others have female heterogamety. [ 15 ]  Sex chromosomes have arisen independently multiple times in angiosperms, from the monoecious ancestral condition. The move from a monoecious to dioecious system requires both  male and female sterility mutations  to be present in the population. Male sterility likely arises first as an adaptation to prevent selfing. Once male sterility has reached a certain prevalence, then female sterility may have a chance to arise and spread. [ 13 ]


In the domesticated papaya ( Carica papaya ), three sex chromosomes are present, denoted as X, Y and Y h . This corresponds with three sexes: females with XX chromosomes, males with XY, and hermaphrodites with XY h . The hermaphrodite sex is estimated to have arisen only 4000 years ago, post-domestication of the plant. The genetic architecture suggests that either the Y chromosome has an X-inactivating gene, or that the Y h  chromosome has an X-activating gene. [ 20 ]


Allosomes not only carry the genes that determine male and female traits, but also those for some other characteristics as well.  Genes that are carried by either sex chromosome are said to be  sex linked . Sex linked diseases are passed down through families through one of the X or Y chromosomes. Since usually men inherit Y chromosomes, they are the only ones to inherit Y-linked traits.  Men and women can get the X-linked ones since both inherit X chromosomes. [ 21 ]


An allele is either said to be  dominant  or  recessive . Dominant inheritance occurs when an abnormal gene from one parent causes disease even though the matching gene from the other parent is normal. The abnormal allele dominates. Recessive inheritance is when both matching genes must be abnormal to cause disease. If only one gene in the pair is abnormal, the disease does not occur, or is mild. Someone who has one abnormal gene (but no symptoms) is called a carrier. A carrier can pass this abnormal gene to his or her children. [ 22 ]  X chromosome carry about 1500 genes, more than any other chromosome in the human body. Most of them code for something other than female anatomical traits. Many of the non-sex determining X-linked genes are responsible for abnormal conditions. The Y chromosome carries about 78 genes. Most of the Y chromosome genes are involved with essential cell house-keeping activities and sperm production. Only one of the Y chromosome genes, the SRY gene, is responsible for male anatomical traits.  When any of the 9 genes involved in sperm production are missing or defective the result is usually very low sperm counts and infertility. [ 23 ]  Examples of mutations on the X chromosome include more common diseases such as the following:


Other complications include:


Sex chromosomes evolve from standard pairs of autosomal chromosomes. [ 27 ]  In a large number of organisms, the sex-determination systems presently observed are products of sex chromosome turnover. Sex chromosome turnover is a process defined as when the type of the sex chromosome changes as a product of a change in the identity of the sex-determining genes (such as by mutation) or by a change in their location. [ 28 ]  In other cases, sex chromosomes may grow substantially with respect to their ancestral forms as a result of fusion events with autosomes, and autosome-sex chromosome fusions result in what are called neo-sex chromosomes. Five examples of this are now known in the songbird superfamily  Sylvioidea . [ 29 ]  There is one experimentally documented case of sex chromosome turnover occurring during a 30-year evolutionary experiment involving  teleost  fish (specifically the  swordtails ), in which hybridization experiments resulted in a translocation of the sex-determiner region of a sex chromosome into an autosome. This resulted in the autosome becoming a novel W sex chromosome. [ 30 ]


Subtelomeres  are segments of DNA between telomeric caps and chromatin.


Telomeres  are specialized  protein – DNA  constructs present at the ends of  eukaryotic  chromosomes, which prevent them from degradation and end-to-end  chromosomal  fusion. Most  vertebrate  telomeric DNA consists of long ( T T A G G G )n repeats of variable length, often around 3-20kb.  Subtelomeres  are segments of DNA between telomeric caps and  chromatin . In vertebrates, each chromosome has two subtelomeres immediately adjacent to the long (TTAGGG)n repeats. Subtelomeres are considered to be the most distal (farthest from the  centromere ) region of unique DNA on a chromosome, and they are unusually dynamic and variable mosaics of multichromosomal blocks of sequence. The subtelomeres of such diverse species as humans,  Plasmodium falciparum ,  Drosophila melanogaster , and  Saccharomyces cerevisiae  are structurally similar in that they are composed of various repeated elements, but the extent of the subtelomeres and the sequence of the elements vary greatly among organisms. [ 1 ]  In yeast ( S. cerevisiae ), subtelomeres are composed of two domains: the proximal and distal (telomeric) domains. The two domains differ in sequence content and extent of homology to other chromosome ends, and they are often separated by a stretch of degenerate telomere repeats (TTAGGG) and an element called 'core X', which is found at all chromosome ends and contains an  autonomously replicating sequence  (ARS) and an ABF1 binding site. [ 2 ] [ 3 ]  The proximal domain is composed of variable interchromosomal duplications (<1-30  kb ); this region can contain genes such  Pho ,  Mel , and  Mal . [ 4 ]  The distal domain is composed of 0-4 tandem copies of the highly conserved Y' element; the number and chromosomal distribution of Y′ elements varies among yeast strains. [ 5 ]  Between the core X and the Y' element or the core X and TTAGGG sequence there is often a set of 4 subtelomeric repeats elements (STR): STR-A, STR-B, STR-C and STR-D which consists of multiple copies of the vertebrate telomeric motif TTAGGG. [ 6 ]  This two-domain structure is remarkably similar to the subtelomere structure in human chromosomes 20p, 4q and 18p in which proximal and distal subtelomeric domains are separated by a stretch of degenerate TTAGGG repeats, but the picture that emerges from studies of the subtelomeres of other human chromosomes indicates that the two-domain model does not apply universally. [ 1 ]


This structure with repeated sequences is responsible for frequent duplication events, which create new genes, and recombination events, at the origin of combination diversity. These properties generate diversity at an individual scale and therefore contribute to adaptation of organisms to their environments. For example, in  Plasmodium falciparum  during  interphase  of the  erythrocytic stage , the chromosomic extremities are gathered at the cell nucleus periphery, where they undergo frequent  deletion  and telomere  position effect  (TPE). This event, in addition to expansion and deletion of subtelomeric repeats, gives rise to chromosome size polymorphisms and thus, subtelomeres undergo  epigenetic  and genetic controls. Because of the properties of subtelomeres,  Plasmodium falciparum  evades host immunity by varying the antigenic and adhesive character of infected erythrocytes (see Subtelomeric transcripts). [ 7 ] [ 8 ]


Variation of subtelomeric regions are mostly variation on STRs, due to  recombination  of large-scale stretches delimited by (TTAGGG)n-like repeated sequences, which play an important role in recombination and transcription.  Haplotype  (DNA sequence variants) and length differences are therefore observed between individuals.


Subtelomeric transcripts largely consist of either  pseudogenes  (transcribed genes producing RNA sequences not translated into protein) or  gene families . In humans, they code for  olfactory receptors ,  immunoglobulin heavy chains , and  zinc-finger proteins . In other species, several parasites such as  Plasmodium  and  Trypanosoma brucei  have developed sophisticated evasion mechanisms to adapt to the hostile environment posed by the host, such as exposing variable surface  antigens  to escape the immune system. Genes coding for surface antigens in these organisms are located at subtelomeric regions, and it has been speculated that this preferred location facilitates gene switching and expression, and the generation of new variants. [ 9 ] [ 10 ]  For example, the genes belonging to the  var  family in  Plasmodium falciparum  (agent of malaria) are mostly localized in subtelomeric regions. Antigenic variation is orchestrated by epigenetic factors, including monoallelic var transcription at separate spatial domains at the nuclear periphery ( nuclear pore ), differential  histone  marks on otherwise identical var genes, and var  silencing  mediated by telomeric  heterochromatin . Other factors such as non-coding RNA produced in subtelomeric regions adjacent or within  var  genes may contribute as well to  antigenic variation . [ 11 ] [ 12 ]  In  Trypanosoma brucei  (agent of sleeping sickness),  variable surface glycoprotein  (VSG) antigenic variation is a relevant mechanism used by the parasite to evade the host immune system. VSG expression is exclusively subtelomeric and occurs either by in situ activation of a silent VSG gene or by DNA rearrangement that inserts an internal silent copy of a VSG gene into an active telomeric expression site. To contrast with  Plasmodium falciparum , in  Trypanosoma brucei , antigenic variation is orchestrated by epigenetic and genetic factors. [ 13 ] [ 14 ]


In  Pneumocystis jirovecii  major surface glycoprotein (MSG) gene family cause antigenic variation. MSG genes are like boxes at chromosome ends, and only the MSG gene at the unique  locus  UCS (upstream conserved sequence) is  transcribed . Different MSG genes can occupy the expression site (UCS), suggesting that  recombination  can take a gene from a pool of silent donors and install it at the expression site, possibly via  crossovers , activating transcription of a new MSG gene, and changing the surface antigen of  Pneumocystis jirovecii . Switching at the expression site is probably facilitated by the subtelomeric locations of expressed and silent MSG genes. A second subtelomeric gene family, MSR, is not strictly regulated at the transcriptional level, but may contribute to phenotypic diversity. Antigenic variation in  P. jirovecii  is dominated by genetic regulation. [ 15 ] [ 16 ]


Loss of telomeric DNA through repeated cycles of cell division is associated with  senescence  or somatic cell aging.  In contrast,  germ line  and  cancer  cells possess an enzyme,  telomerase , which prevents telomere degradation and maintains telomere integrity, causing these types of cells to be very long-lived.


In humans, the role of subtelomere disorders is demonstrated in  facioscapulohumeral muscular dystrophy  (FSHD),  Alzheimer's disease ,  epilepsy [ 17 ]  and peculiar syndromic diseases ( malformation  and mental retardation). For example, FSHD is associated with a deletion in the subtelomeric region of chromosome 4q. A series of 10 to >100 kb repeats is located in the normal 4q subtelomere, but FSHD patients have only 1–10 repeat units. This deletion is thought to cause disease owing to a position effect that influences the transcription of nearby genes, rather than through the loss of the repeat array itself. [ 1 ]


Subtelomeres are homologous to other subtelomeres that are located at different chromosomes and are a type of  transposable element , DNA segments that can move around the genome. Although subtelomeres are  pseudogenes  and do not code for protein, they provide an evolutionary advantage by diversifying genes. The duplication, recombination, and deletion of subtelomeres allow for the creation of new genes and new chromosomal properties. [ 1 ]  The advantages of subtelomeres have been studied in different species such as  Plasmodium falciparum , [ 1 ]   Drosophila melanogaster , [ 1 ]  and  Saccharomyces cerevisiae , [ 1 ]  since they have similar genetic elements to humans, not accounting for length and sequence. [ 1 ]  Subtelomeres might have the same role in plants since the same advantage have been found in a common bean plant known as  Phaseolus vulgaris . [ 18 ]


Different varieties of subtelomeres are frequently rearranging during meiotic and mitotic recombination, indicating that subtelomeres are frequently shuffling, which causes new and rapid genetic changes in chromosomes. [ 1 ]  In  Saccharomyces cerevisiae , 15kb region of chromosome 7L in subtelomeres maintained cell viability in the removal of telomerase, while the removal of the last 15kb increased chromosome  senescence . [ 19 ]  The knockout of subtelomeres in fission yeast,  Schizosaccharomyces pombe , cells does not impede mitosis and meiosis from occurring, indicating that subtelomeres are not necessary for cell division. [ 20 ]  They are not needed for the procession of mitosis and meiosis yet, subtelomeres take advantage of cellular DNA recombination. The knockout of subtelomeres in  Schizosaccharomyces pombe  cells does not affect the regulation of multiple stress responses, when treated with high doses of  hydroxyurea ,  camptothecin ,  ultraviolet radiation , and  thiabendazole . [ 20 ]  Knockout of Subtelomeres in   Schizosaccharomyces pombe  cells did not affect the length of telomeres, indicating that they play no role it the regulation of length. [ 20 ]  However, subtelomeres strongly influences the replication timing of telomeres. [ 21 ]  Knockout of subtelomeres in  Schizosaccharomyces pombe  cells after the loss of telomerase does not affect cell survival, indicating that subtelomeres are not necessary for cell survival. [ 20 ]  An explanation as to why subtelomeres are not necessary after the loss of telomerase is because the chromosomes can use intra or inter-chromosomal circularization [ 22 ]  or HAATI [ 23 ]  to maintain chromosomal stabilization. However, the use of inter-chromosomal circularization engenders chromosome instability by creating two  centromeres  in a single chromosome, causing chromosomal breakage during mitosis. In response to this, the chromosome could induce centromere inactivation to impede the formation of two centromeres, but this would induce  heterochromatin  formation in centromeres. Heterochromatin can be deleterious if it gets into a location that it is not supposed to be in. Subtelomeres are responsible to block heterochromatin from getting into the  euchromatin  region. Subtelomeres can mitigate the effects of heterochromatin invasion, by distributing heterochromatin around the ends of the subtelomeres. Without subtelomeres, heterochromatin would spread around the region of subtelomeres, getting too close to important genes. At this distance, heterochromatin can silence genes that are nearby, resulting in a higher sensitivity to  osmotic stress . [ 20 ]


Subtelomeres carry out essential functions with  Shugoshin protein . Shugoshin is a centromere protein for chromosome segregation during meiosis and mitosis. There are two types of Shugoshin protein:  SGOL1  and  SGOL2 . Sgo1 is only expressed in meiosis 1 for centromeric cohesion of the sister chromosomes, [ 24 ]  while Sgo2,  expressed in meiosis and mitosis, is responsible for the segregation of chromosomes at centromeres in the M phase. In fission yeast, Sgo2 is localized not only in centromeres, but also in subtelomeres. Sgo2 interacts with subtelomeres during interphase; middle of the G2 phase and plays a major role in forming "knob", which is a highly condensed chromatin body. Sgo2 remains in subtelomeres, whose cells lack telomere DNA. Sgo2 represses the expression of subtelomeric genes that is in a different pass-way from the  H3K9me3 - Swi6-mediated heterochromatin. Sgo2 has also repressive effects for timing of subtelomeres replication by suppressing Sld3, [ 25 ]  a replication factor, at the start of the replication. [ 26 ]  Thus, Sgo2 regulate gene expressions and replication to ensure proper subtelomeric gene expression and replication timing.


Subtelomere analysis, especially sequencing and profiling of patient subtelomeres, is difficult because of the repeated sequences, length of stretches, and lack of databases on the topic.


[ original research? ]


Syntelic attachment  occurs when both sister  chromosomes  are attached to a single  spindle pole . [ 1 ] [ 2 ]


Normal  cell division  distributes the genome equally between two daughter cells, with each chromosome attaching to an ovoid structure called the spindle. During the division process, errors commonly occur in attaching the chromosomes to the spindle, estimated to affect 86 to 90 percent of chromosomes. [ 3 ]


Such attachment errors are common during the early stages of spindle formation, but they are mostly corrected before the start of  anaphase . [ 4 ]
Successful cell division requires identification and correction of any dangerous errors before the cell splits in two. [ 3 ]
If the syntelic attachment continues, it causes both sister  chromatids  to be segregated to a single daughter cell. [ 5 ]


Microtubules  extend from the  spindle poles  and attach to the first  kinetochore  they encounter. [ 6 ]  Because this process is stochastic and not facilitated or directed, the first microtubules to come into contact with a kinetochore may not have originated at the correct spindle pole. [ 7 ]  Normally, the sister kinetochores are on opposing sides of the  chromosomes , facing outward toward their respective spindle poles. [ 8 ]  This arrangement enhances the likelihood of properly bi-oriented chromosomes and is sometimes referred to as a mechanism for 'avoidance' of syntelic attachment. [ 8 ] [ 9 ]  However, sometimes the kinetochores are found on the same side of the  centromere , and this error cannot be corrected stochastically. [ 8 ]  Instead, the spindle must actively exert forces on one of the two kinetochores to relocate it to the proper, outer edge of the centromere. [ 8 ]  If the geometry and orientation of the two kinetochores is not corrected, the cells can still effectively achieve bi-orientation through the employment of error correction mechanisms. [ 9 ]


Polyploid  cells, and  tetraploids  in particular, experience an increased number of syntelic attachments, which contributes to their  genomic instability . [ 10 ]  This phenomenon of increased rates of syntelic attachment in polyploids is thought to result from an inability to scale the mitotic spindle and kinetochore architecture to accommodate the increase in cell size. [ 10 ]  Therefore, scaling defects between the genome and cellular architecture, which often occur in  cancer , likely result in high rates of syntelic attachment. [ 10 ]


Error correction is closely tied to the  spindle assembly checkpoint  (SAC), which oversees the progression through  mitosis  and can halt the cell in  metaphase  until proper bi-orientation of all chromosomes is achieved. [ 11 ]  Initial attachments occur randomly, and the cell destabilizes any incorrect microtubule-kinetochore interactions. Subsequent rounds of undirected attachment and destabilization occur until each kinetochore is attached to the correct spindle pole.


Tension  was quickly identified as an important component of the error-sensing mechanism and likely of the spindle assembly checkpoint. [ 6 ] [ 11 ]  Ipl1 in  yeast  and its functional  homolog ,  Aurora B , in  metazoans  aid in tension detection and destabilization of errant attachments. [ 11 ] [ 12 ]  Aurora B is found at the centromere, between the two kinetochores. [ 11 ]  In the absence of tension, Aurora B can  phosphorylate  substrates at the kinetochores, leading to destabilization of the attached microtubules. [ 11 ]  Properly attached microtubules induce tension, pulling the kinetochore far enough away from Aurora B so as to prevent phosphorylation of kinetochore components. [ 11 ]  Following destabilization, the kinetochore can form new spindle attachments, and if the new attachments result in chromosome bi-orientation, they will remain. [ 12 ]  Correct attachments that induce tension are more likely to occur when the kinetochores are geometrically positioned on opposite sides of the centromere. [ 7 ]


Robust destabilization by Ipl1/Aurora B in the absence of tension leads to a specific challenge: the initial establishment of bi-orientation, prior to the buildup of tension, would be sensitive to Ipl1/Aurora B activity. [ 13 ]  This is referred to as the initiation problem of biorientation (IPBO), and is resolved by implementing a delay between sensing the tension and destabilizing the attachment. [ 13 ]  Modeling has indicated that such a delay could be introduced if the rate of Ipl1/Aurora B  kinase  activity is slower than that of the counteracting  phosphatase  activity at the kinetochore. [ 13 ]  The time delay allows for tension to be established at bi-oriented chromosomes, so that only syntelic attachments are phosphorylated and destabilized. [ 13 ]


Syntelic attachment is not uncommon in early  metaphase , and can often be resolved by error correction mechanisms that are well-conserved across  metazoans . [ 12 ]  If syntelic attachment is left uncorrected, for example if the  spindle assembly checkpoint  does not successfully pause cells in metaphase, the  chromosomes  will not segregate correctly. [ 12 ]  This failure to properly segregate results in  aneuploidy , which can lead to errors in  development  or  cancer . [ 14 ]  Interestingly, segregation errors that result from syntelic attachment often occur without visible  lagging . [ 15 ]  In contrast, merotelic attachments will cause chromosome lagging during  anaphase , but will often segregate correctly and not result in aneuploidy. [ 14 ] [ 15 ]


A  telomere  ( / ˈ t ɛ l ə m ɪər ,   ˈ t iː l ə -/ ;  from  Ancient Greek     τέλος  ( télos )  'end' and    μέρος  ( méros )  'part') is a region of repetitive  nucleotide  sequences associated with specialized proteins at the ends of linear  chromosomes  (see  Sequences ). Telomeres are a widespread genetic feature most commonly found in  eukaryotes . In most, if not all species possessing them, they protect the terminal regions of  chromosomal DNA  from progressive degradation and ensure the integrity of linear chromosomes by preventing  DNA repair  systems from mistaking the very ends of the DNA strand for a  double-strand break .


The existence of a special structure at the ends of chromosomes was independently proposed in 1938 by  Hermann Joseph Muller , studying the fruit fly  Drosophila melanogaster , and in 1939 by  Barbara McClintock , working with maize. [ 1 ]  Muller observed that the ends of irradiated fruit fly chromosomes did not present alterations such as deletions or inversions. He hypothesized the presence of a protective cap, which he coined "telomeres", from the Greek  telos  (end) and  meros  (part). [ 2 ]


In the early 1970s, Soviet theorist  Alexey Olovnikov  first recognized that chromosomes could not completely replicate their ends; this is known as the "end replication problem". Building on this, and accommodating  Leonard Hayflick 's idea of limited  somatic cell  division, Olovnikov suggested that DNA sequences are lost every time a cell replicates until the loss reaches a critical level, at which point cell division ends. [ 3 ] [ 4 ] [ 5 ]  According to his theory of marginotomy, DNA sequences at the ends of telomeres are represented by tandem repeats, which create a buffer that determines the number of divisions that a certain cell clone can undergo. Furthermore, it was predicted that a specialized DNA polymerase (originally called a tandem-DNA-polymerase) could extend telomeres in immortal tissues such as germ line, cancer cells and stem cells. It also followed from this hypothesis that organisms with circular genome, such as bacteria, do not have the end replication problem and therefore do not age.


Olovnikov suggested that in germline cells, cells of vegetatively propagated organisms, and immortal cell populations such as most cancer cell lines, an enzyme might be activated to prevent the shortening of DNA termini with each cell division. [ 6 ] [ 7 ]


In 1975–1977,  Elizabeth Blackburn , working as a postdoctoral fellow at  Yale University  with  Joseph G. Gall , discovered the unusual nature of telomeres, with their simple repeated DNA sequences composing chromosome ends. [ 8 ]  Blackburn,  Carol Greider , and  Jack Szostak  were awarded the  2009   Nobel Prize in Physiology or Medicine  for the discovery of how chromosomes are protected by telomeres and the  enzyme   telomerase . [ 9 ]


During DNA replication,  DNA polymerase  cannot replicate the sequences present at the  3' ends  of the parent strands. This is a consequence of its unidirectional mode of DNA synthesis: it can only attach new nucleotides to an existing 3'-end (that is, synthesis progresses 5'-3') and thus it requires a  primer  to initiate replication. On the leading strand (oriented 5'-3' within the replication fork), DNA-polymerase continuously replicates from the point of initiation all the way to the strand's end with the primer (made of  RNA ) then being excised and substituted by DNA. The lagging strand, however, is oriented 3'-5' with respect to the replication fork so continuous replication by DNA-polymerase is impossible, which necessitates discontinuous replication involving the repeated synthesis of primers further 5' of the site of initiation (see  lagging strand replication ). The last primer to be involved in lagging-strand replication sits near the 3'-end of the template (corresponding to the potential 5'-end of the lagging-strand). Originally it was believed that the last primer would sit at the very end of the template, thus, once removed, the DNA-polymerase that substitutes primers with DNA (DNA-Pol δ in eukaryotes) [ note 1 ]  would be unable to synthesize the "replacement DNA" from the 5'-end of the lagging strand so that the template nucleotides previously paired to the last primer would not be replicated. [ 10 ]  It has since been questioned whether the last lagging strand primer is placed exactly at the 3'-end of the template and it was demonstrated that it is rather synthesized at a distance of about 70–100 nucleotides which is consistent with the finding that DNA in cultured human cell is shortened by 50–100  base pairs  per  cell division . [ 11 ]


If coding sequences are degraded in this process, potentially vital genetic code would be lost. Telomeres are non-coding, repetitive sequences located at the termini of linear chromosomes to act as buffers for those coding sequences further behind. They "cap" the end-sequences and are progressively degraded in the process of DNA replication.


The "end replication problem" is exclusive to linear chromosomes as circular chromosomes do not have ends lying without reach of DNA-polymerases. Most  prokaryotes , relying on circular chromosomes, accordingly do not possess telomeres. [ 12 ]  A small fraction of  bacterial  chromosomes (such as those in  Streptomyces ,  Agrobacterium , and  Borrelia ), however, are linear and possess telomeres, which are very different from those of the eukaryotic chromosomes in structure and function. The known structures of bacterial telomeres take the form of  proteins  bound to the ends of linear chromosomes, or hairpin loops of single-stranded DNA at the ends of the linear chromosomes. [ 13 ]


At the very 3'-end of the telomere there is a 300 base pair overhang which can invade the double-stranded portion of the telomere forming a structure known as a T-loop. This loop is analogous to a knot, which stabilizes the telomere, and prevents the telomere ends from being recognized as breakpoints by the DNA repair machinery. Should non-homologous end joining occur at the telomeric ends, chromosomal fusion would result. The T-loop is maintained by several proteins, collectively referred to as the shelterin complex. In humans, the shelterin complex consists of six proteins identified as  TRF1 ,  TRF2 ,  TIN2 ,  POT1 ,  TPP1 , and  RAP1 . [ 14 ]  In many species, the sequence repeats are enriched in  guanine , e.g. TTAGGG in  vertebrates , [ 15 ]  which allows the formation of  G-quadruplexes , a special conformation of DNA involving non-Watson-Crick base pairing. There are different subtypes depending on the involvement of single- or double-stranded DNA, among other things. There is evidence for the 3'-overhang in  ciliates  (that possess telomere repeats similar to those found in  vertebrates ) to form such G-quadruplexes that accommodate it, rather than a T-loop. G-quadruplexes present an obstacle for enzymes such as DNA-polymerases and are thus thought to be involved in the regulation of replication and transcription. [ 16 ]


Many organisms have a ribonucleoprotein enzyme called telomerase, which carries out the task of adding repetitive nucleotide sequences to the ends of the DNA. Telomerase "replenishes" the telomere "cap" and requires no ATP. [ 17 ]  In most multicellular eukaryotic organisms, telomerase is active only in  germ cells , some types of  stem cells  such as  embryonic stem cells , and certain  white blood cells . Telomerase can be reactivated and telomeres reset back to an embryonic state by  somatic cell nuclear transfer . [ 18 ]  The steady shortening of telomeres with each replication in somatic (body) cells may have a role in  senescence [ 19 ]  and in the prevention of  cancer . [ 20 ] [ 21 ]  This is because the telomeres act as a sort of time-delay "fuse", eventually running out after a certain number of cell divisions and resulting in the eventual loss of vital genetic information from the cell's chromosome with future divisions. [ 22 ] [ 23 ]


Telomere length varies greatly between species, from approximately 300  base pairs  in yeast [ 24 ]  to many kilobases in humans, and usually is composed of arrays of  guanine -rich, six- to eight-base-pair-long repeats. Eukaryotic telomeres normally terminate with  3′ single-stranded-DNA overhang  ranging from 75 to 300 bases, which is essential for telomere maintenance and capping. Multiple proteins binding single- and double-stranded telomere DNA have been identified. [ 25 ]  These function in both telomere maintenance and capping. Telomeres form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a long circle, stabilized by  telomere-binding proteins . [ 26 ]  At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA, and base pairing to one of the two strands. This triple-stranded structure is called a  displacement loop  or D-loop. [ 27 ]


Apart from the end replication problem,  in vitro  studies have shown that telomeres accumulate damage due to  oxidative stress  and that oxidative stress-mediated DNA damage has a major influence on telomere shortening  in vivo . There is a multitude of ways in which oxidative stress, mediated by  reactive oxygen species  (ROS), can lead to DNA damage; however, it is yet unclear whether the elevated rate in telomeres is brought about by their inherent susceptibility or a diminished activity of DNA repair systems in these regions. [ 28 ]  Despite widespread agreement of the findings, widespread flaws regarding measurement and sampling have been pointed out; for example, a suspected species and tissue dependency of oxidative damage to telomeres is said to be insufficiently accounted for. [ 29 ]  Population-based studies have indicated an interaction between anti-oxidant intake and telomere length. In the Long Island Breast Cancer Study Project (LIBCSP), authors found a moderate increase in breast cancer risk among women with the shortest telomeres and lower dietary intake of beta carotene, vitamin C or E. [ 30 ]  These results  [ 31 ]  suggest that cancer risk due to telomere shortening may interact with other mechanisms of DNA damage, specifically oxidative stress.


Although telomeres shorten during the lifetime of an individual, it is telomere shortening-rate rather than telomere length that is associated with the lifespan of a species. [ 32 ]  Critically short telomeres trigger a  DNA damage  response and  cellular senescence . [ 32 ]  Mice have much longer telomeres, but a greatly accelerated telomere shortening-rate and greatly reduced lifespan compared to humans and elephants. [ 33 ]


Telomere shortening is associated with aging, mortality, and aging-related diseases in experimental animals. [ 8 ] [ 34 ]  Although many factors can affect human lifespan, such as smoking, diet, and exercise, as persons approach the upper limit of human  life expectancy , longer telomeres may be associated with lifespan. [ 35 ]


Meta-analyses  found that increased perceived  psychological stress  was associated with a small decrease in telomere length—but that these associations attenuate to no significant association when accounting for  publication bias . The literature concerning telomeres as integrative biomarkers of exposure to stress and adversity is dominated by cross-sectional and correlational studies, which makes causal interpretation problematic. [ 31 ] [ 36 ]  A 2020 review argued that the relationship between psychosocial stress and telomere length appears strongest for stress experienced in utero or early life. [ 37 ]


The phenomenon of limited cellular division was first observed by  Leonard Hayflick , and is now referred to as the  Hayflick limit . [ 38 ] [ 39 ]  Significant discoveries were subsequently made by a group of scientists organized at  Geron Corporation  by Geron's founder  Michael D. West , that tied telomere shortening with the Hayflick limit. [ 40 ]  The cloning of the catalytic component of telomerase enabled experiments to test whether the expression of telomerase at levels sufficient to prevent telomere shortening was capable of immortalizing human cells. Telomerase was demonstrated in a 1998 publication in  Science  to be capable of extending cell lifespan, and now is well-recognized as capable of immortalizing human somatic cells. [ 41 ]


Two studies on long-lived  seabirds  demonstrate that the role of telomeres is far from being understood. In 2003, scientists observed that the telomeres of  Leach's storm-petrel  ( Oceanodroma leucorhoa ) seem to lengthen with chronological age, the first observed instance of such behaviour of telomeres. [ 42 ]


A study reported that telomere length of different mammalian species correlates inversely rather than directly with lifespan, and  concluded that the contribution of telomere length to lifespan remains controversial. [ 43 ]  There is little evidence that, in humans, telomere length is a significant biomarker of normal aging with respect to important cognitive and physical abilities. [ 44 ]


Experimentally verified and predicted telomere sequence motifs from more than 9000 species are collected in research community curated database  TeloBase . [ 45 ]  Some of the experimentally verified telomere  nucleotide  sequences are also listed in  Telomerase Database  website (see  nucleic acid notation  for letter representations).


Preliminary research indicates that disease risk in aging may be associated with telomere shortening,  senescent cells , or SASP ( senescence-associated secretory phenotype ). [ 32 ]


Several techniques are currently employed to assess average telomere length in eukaryotic cells. One method is the Terminal Restriction Fragment (TRF) southern blot. [ 49 ] [ 50 ]  There is a Web-based Analyser of the Length of Telomeres ( WALTER ), software processing the TRF pictures. [ 51 ]  A Real-Time  PCR  assay for telomere length involves determining the Telomere-to-Single Copy Gene (T/S) ratio, which is demonstrated to be proportional to the average telomere length in a cell. [ 52 ]


Tools have also been developed to estimate the length of telomere from  whole genome sequencing  (WGS) experiments. Amongst these are TelSeq, [ 53 ]  Telomerecat [ 54 ]  and telomereHunter. [ 55 ]  Length estimation from WGS typically works by differentiating telomere sequencing reads and then inferring the length of telomere that produced that number of reads. These methods have been shown to correlate with preexisting methods of estimation such as PCR and TRF.  Flow-FISH  is used to quantify the length of telomeres in human white blood cells. A semi-automated method for measuring the average length of telomeres with Flow FISH was published in Nature Protocols in 2006. [ 56 ]


While multiple companies offer telomere length measurement services, the utility of these measurements for widespread clinical or personal use has been questioned. [ 57 ] [ 58 ]  Nobel Prize winner  Elizabeth Blackburn , who was co-founder of one company, promoted the clinical utility of telomere length measures. [ 59 ]


During the last two decades, eco-evolutionary studies have investigated the relevance of life-history traits and environmental conditions on telomeres of wildlife. Most of these studies have been conducted in  endotherms , i.e. birds and mammals. They have provided evidence for the inheritance of telomere length; however,  heritability  estimates vary greatly within and among species. [ 60 ]  Age and telomere length often negatively correlate in vertebrates, but this decline is variable among taxa and linked to the method used for estimating telomere length. [ 61 ]  In contrast, the available information shows no sex differences in telomere length across vertebrates. [ 62 ]  Phylogeny and life history traits such as body size or the pace of life can also affect telomere dynamics. For example, it has been described across species of birds and mammals. [ 63 ]  In 2019, a meta-analysis confirmed that the exposure to stressors (e.g. pathogen infection, competition, reproductive effort and high activity level) was associated with shorter telomeres across different animal taxa. [ 64 ]


Studies on  ectotherms , and other non-mammalian organisms, show that there is no single universal model of telomere erosion; rather, there is wide variation in relevant dynamics across  Metazoa , and even within smaller taxonomic groups these patterns appear diverse. [ 65 ]


TERRA  in biology is an abbreviation for "TElomeric Repeat-containing RNA". [ 1 ]  TERRA is  RNA  that is  transcribed  from  telomeres  — the repeating 6- nucleotide  sequences that cap the ends of  chromosomes . TERRA functions with  shelterin  to inhibit telomere lengthening by enzyme  telomerase . [ 1 ]  However, other studies have shown that under certain conditions TERRA can recruit telomerase to telomeres. [ 2 ]


TERRAs are essential for telomere length and maintenance. [ 3 ] [ 2 ]  At least four factors contribute to telomere maintenance: telomerase, shelterin, TERRA and the  CST Complex . [ 4 ]


TERRA can also regulate telomere length by increasing  euchromatin  formation. [ 5 ]  On the other hand,  nonsense-mediated decay  factor enrichment at telomeres may exist to prevent TERRA inhibition of telomerase. [ 1 ]  TERRA levels vary during the  cell cycle , decreasing during  S phase , and increasing in the transition from  G2 phase  to  G1 phase . [ 5 ]


Vaginoplasty  is any surgical procedure that results in the construction or reconstruction of the  vagina . It is a type of  genitoplasty .  Pelvic organ prolapse  is often treated with one or more surgeries to repair the vagina. Sometimes a vaginoplasty is needed following the treatment or removal of  malignant growths  or  abscesses  to restore a normal vaginal structure and function. Surgery to the vagina is done to correct  congenital defects  to the vagina,  urethra   and  rectum . It may correct protrusion of the  urinary bladder  into the vagina ( cystocele ) and protrusion of the rectum ( rectocele ) into the vagina. [ 1 ]  Often, a vaginoplasty is performed to repair the vagina and its attached structures due to trauma or injury.


Congenital disorders  such as  adrenal hyperplasia  can affect the structure and function of the vagina and sometimes the vagina is absent; these can be reconstructed or formed, using a vaginoplasty. [ 2 ]  Other candidates for the surgery include babies born with a microphallus, people with  Müllerian agenesis  resulting in  vaginal hypoplasia ,  trans women , and women who have had a vaginectomy after malignancy or trauma. [ 3 ] [ 4 ]


Vaginoplasty is the description of the following surgical interventions:


In some instances, extra tissue is needed to reconstruct or construct the vagina. These grafts used in vaginoplasty can be an  allotransplantation , a  heterograft , or an  autologous  material. [ 9 ] [ 10 ]  A woman can use an autologous in vitro cultured tissue taken from her vaginal vestibule as transplanted tissue to form the lining of the reconstructed vagina. [ 9 ]  A reconstructed or newly constructed vagina is called a  neovagina . [ 11 ]


Conditions such as  congenital adrenal hyperplasia  virilize genetic females due to a  21-hydroxylase  deficiency. Specific procedures include: clitoral reduction,  labiaplasty , normalizing appearance, vagina creation, initiating vaginal dilation. [ 12 ]   Vaginal atresia , or congenital absence of the vagina, can be another reason for surgery to construct a normal and functional vagina. [ 13 ]  Vaginoplasty is used as part of the series of surgeries needed to treat those girls and women born with the  bladder located outside of their abdomen . After the repairs, women have been able to give birth but are at risk of prolapse. [ 1 ]


There are human rights concerns about vaginoplasties and other genital surgeries in children who are not old enough to consent, [ 14 ] [ 15 ]  including concern with post-surgical sexual function, [ 16 ]  and assumptions of  cisnormativity . [ 17 ]  There is no consensus attitude among clinicians about their necessity, timing, method or evaluation. [ 12 ]  Vaginoplasties may be performed in children or adolescents with  intersex  conditions or  disorders of sex development . [ 18 ]


Non-surgical vagina creation was used in the past to treat the  congenital  absence of a vagina. The procedure involved the wearing of a saddle-like device and the use of increasing-diameter  dilators . The procedure took several months and was sometimes painful. It was not effective in every instance. [ 2 ]  Uncommon growths, cysts, septums in the vagina can also require vaginoplasty. [ 19 ]


Radiological cancer treatment  can result in the destruction or alteration of vaginal tissues. Vaginoplasty is often performed to reconstruct the vagina and other genital structures. In some cases, normal sexual function can be restored. [ 3 ]


A canal is surgically constructed between the  urinary bladder  and  urethra  in the anterior portion of the pelvic region and the  rectum . A skin graft is used from another area of the person's body. The graft is removed from the  thigh ,  buttocks , or  inguinal  region. Other materials have been used to create the lining of the new vagina. These have been cutaneous  skin flaps ,  amniotic membranes , and  buccal mucosa . [ 3 ] [ 9 ]


Several techniques may be used in  gender-affirming surgery   to create a neovagina.


Inversion of the penile skin is the method most often selected to create a neovagina by surgeons performing gender-affirming surgery. The inverted penile skin uses inferior pedicle skin or abdominal skin for the lining of the neovagina. The skin is cut to form an appropriate-sized flap. The skin flap is sometimes combined with a scrotal or urethral flap. [ 4 ]


The penile inversion technique was pioneered by  Georges Burou  in his Morocco clinic in the 1950s. [ 20 ]   By the 1970s he had performed hundreds of them, and gave his first public presentation of his technique to a conference at Stanford University in 1973, [ 21 ]  after which it gradually became the predominant technique worldwide.


Bowel vaginoplasty is another common vaginoplasty technique. It is also used for vaginoplasty in cisgender women. [ 22 ]  As with penile inversion vaginoplasty, the testicles and scrotum are removed, the glans made into a clitoris, and the neovulva constructed from scrotal, penile and urethral tissue. However, in bowel vaginoplasty a segment of  rectosigmoid colon  is grafted into a surgically created canal to form the neovagina. [ 23 ]


Transgender peritoneal vaginoplasty,  a.k.a.  peritoneal pull-down or pull-through (PPT), is based on neovaginal techniques documented in the 1970s and 80s [ 25 ] [ 26 ] [ 27 ]  for cisgender women born without a vaginal canal due to  agenesis / atresia , [ 28 ] [ 29 ]  which were referred to as the "Davydov" procedure [ 29 ] [ 30 ]  or "Rothman's" method. [ 31 ]  A 2022 review states, "In the last 5 years, peritoneal flap vaginoplasty has emerged as a promising technique". [ 32 ]


This form of vaginoplasty utilizes tissue of the  peritoneum  to form the canal lining of the neovagina. [ 33 ] [ 29 ]


For trans women who had their  puberty blocked , insufficient penile and scrotal skin may be available for traditional penile inversion. In such cases, peritoneal vaginoplasty remedies the issue of insufficient tissue. [ 33 ] [ 28 ] [ 29 ] [ 34 ]  Peritoneal vaginoplasty can be used as a surgical revision to increase or restore vaginal depth in persons who have had a previous vaginoplasty. [ 33 ] [ 29 ] [ 34 ] [ 35 ] [ 36 ]


Penile- scrotal  skin flaps are also used. Nongenital full-thickness graft (FTG) or split-thickness skin grafts from other parts of the body have been used. [ citation needed ]


Critics have labeled such surgery as the "designer vagina". The  American College of Obstetricians and Gynecologists  issued a warning against these procedures in 2007 [ 38 ]  as did the  Royal Australian and New Zealand College of Obstetricians and Gynaecologists , [ 39 ]  and a commentary in the  British Medical Journal  strongly criticized the "designer vagina" in 2009. [ 39 ] [ 40 ]   The  Society of Obstetricians and Gynaecologists of Canada  published a policy statement against elective vaginoplasty based upon the risks associated with unnecessary cosmetic surgery in 2013. [ 41 ]


The World Health Organization describes any medically unnecessary surgery to the vaginal tissue and organs as  female genital mutilation . [ 42 ]


Vaginal rejuvenation is a form of elective plastic surgery. Its purpose is to restore or enhance the vagina's cosmetic appearance. [ 40 ]


An  imperforate hymen  is the presence of tissue that completely covers the vaginal opening. It is cut to allow menstrual flow to exit during a short surgical procedure. [ 1 ]  A  hymenorrhaphy  is the surgical procedure that reconstructs the hymen.


In this procedure, a  Foley catheter  is  laparoscopically  inserted to the rectouterine pouch whereupon gradual traction and distension are applied to create a neovagina. [ citation needed ]


In treating  Müllerian agenesis , the Vecchietti procedure is a  laparoscopic  surgical technique that produces a  vagina  of dimensions (depth and width) comparable to those of a normal vagina (ca. 8 cm deep). [ 43 ] [ 44 ]  A small, plastic sphere called an olive is threaded ( sutured ) against the vaginal area; the threads are drawn though the vaginal skin, up through the  abdomen , and through the  navel . There, the threads are attached to a traction device, and then daily are drawn tight so that the olive is pulled inwards and stretches the vagina, by approximately 1 cm per day, thereby creating a vagina, approximately 7 cm deep by 7 cm wide, in 7 days. The mean operating room (OR) time for the Vecchietti vaginoplasty is approximately 45 minutes; yet, depending upon the patient and her indications, the procedure might require more time. [ 45 ]  The outcomes of Vecchietti technique via the laparoscopic approach are found to be comparable to the procedure using laparotomy. [ 46 ]  In  vaginal hypoplasia , traction vaginoplasty such as the Vecchietti technique seems to have the highest success rates both anatomically (99%) and functionally (96%) among available treatments. [ 47 ] [ 19 ]


Other surgical techniques that have been developed include ileal neovagina (Monti's technique), Creatsas vaginoplasty, Wharton–Sheares–George neovaginoplasty, or the Davydov procedure. The most widely used is the Vecchietti laparoscopic procedure. Sometimes sexual intercourse can result in the dilation of a newly constructed vagina. [ 9 ]


The most techniques of vaginoplasty are using inflatable vaginal expanders or vaginal stents to design the vaginal diameter and length. [ 48 ] [ 49 ]  At the end of the procedure the device stays in place to maintain the neovagina against the pelvic wall which also favors the process of microscopic neovascularization and reduces the risks of hematoma. In post-operative setting the expander can be used regularly to prevent post-operative vaginal retraction. [ 50 ]  Solid vaginal dilators can also be used immediately after surgery to keep the passage from attachments, and regularly thereafter to maintain the viability of the neovagina. The frequency required to use decreases over time, however remains obligatory lifelong. [ 51 ] [ 52 ]


Reconstructive vaginoplasty in children and adolescents carries the risk of  superinfection . [ 19 ]


In adults, rates and types of  complications  varied with gender-affirming surgery.  Necrosis  of the clitoral region was 1–3%. Necrosis of the surgically created vagina was 3.7–4.2%. Vaginal shrinkage occurred was documented in 2–10% of those treated.  Stricture , or narrowing of the vaginal orifice was reported in 12–15% of the cases. Of those reporting stricture, 41% underwent a second operation to correct the condition. Necrosis of two  scrotal  flaps has been described. Posterior vaginal wall is a rare complication.  Genital pain  was reported in 4–9%. Rectovaginal  fistula  is also rare with 1% documented. Vaginal prolapse was seen in 1–2% of people  assigned male at birth  undergoing this procedure. [ 4 ]


The ability of emptying the  bladder  was affected for some patients after this procedure: 13% reported improvement, 68% said that there was no change and 19% reported that  voiding  got worse. Those reporting a negative outcome who experienced loss of bladder control and  urinary incontinence  were 19%.  Urinary tract infections  occurred in 32% of those treated. [ 4 ]


Reports of people seeking vaginoplasty go back to the 2nd century. [ 53 ] [ 54 ]   The first modern vaginoplasty was performed in 1931 on  Dora Richter . [ 53 ] [ 55 ] [ 56 ]   Lili Elbe  also underwent a vaginoplasty the same year. [ 57 ]


The  X chromosome  is one of the two  sex chromosomes  in many organisms, including mammals, and is found in both males and females. It is a part of the  XY sex-determination system  and  XO sex-determination system . The X chromosome was named for its unique properties by early researchers, which resulted in the naming of its counterpart  Y chromosome , for the next letter in the alphabet, following its subsequent discovery. [ 3 ]


It was first noted that the X chromosome was special in 1890 by  Hermann Henking  in Leipzig. Henking was studying the testicles of   Pyrrhocoris  and noticed that one chromosome did not take part in  meiosis . Chromosomes are so named because of their ability to take up  staining  ( chroma  in Greek means  color ). Although the X chromosome could be stained just as well as the others, Henking was unsure whether it was a different class of the object and consequently named it  X element , [ 4 ]  which later became X chromosome after it was established that it was indeed a chromosome. [ 5 ]


The idea that the X chromosome was named after its similarity to the letter "X" is mistaken. All chromosomes normally appear as an amorphous blob under the microscope and take on a well-defined shape only during mitosis. This shape is vaguely X-shaped for all chromosomes. It is entirely coincidental that the  Y chromosome , during  mitosis , has two very short branches which can look merged under the microscope and appear as the descender of a Y-shape. [ 6 ]


It was first suggested that the X chromosome was involved in sex determination by  Clarence Erwin McClung  in 1901. After comparing his work on  locusts  with Henking's and others, McClung noted that only half the sperm received an X chromosome. He called this chromosome an  accessory chromosome , and insisted (correctly) that it was a  proper  chromosome, and theorized (incorrectly)  that it was the male-determining chromosome. [ 4 ]


Luke Hutchison  noticed that a number of possible ancestors on the X chromosome inheritance line at a given ancestral generation follows the  Fibonacci sequence . [ 7 ]  A male individual has an X chromosome, which he received from his mother, and a  Y chromosome , which he received from his father. The male counts as the "origin" of his own X chromosome (

 F

 1

 =
 1

 {\displaystyle F_{1}=1}

 ), and at his parents' generation, his X chromosome came from a single parent (

 F

 2

 =
 1

 {\displaystyle F_{2}=1}

 ). The male's mother received one X chromosome from her mother (the son's maternal grandmother), and one from her father (the son's maternal grandfather), so two grandparents contributed to the male descendant's X chromosome (

 F

 3

 =
 2

 {\displaystyle F_{3}=2}

 ). The maternal grandfather received his X chromosome from his mother, and the maternal grandmother received X chromosomes from both of her parents, so three great-grandparents contributed to the male descendant's X chromosome (

 F

 4

 =
 3

 {\displaystyle F_{4}=3}

 ). Five great-great-grandparents contributed to the male descendant's X chromosome (

 F

 5

 =
 5

 {\displaystyle F_{5}=5}

 ), etc. (Note that this assumes that all ancestors of a given descendant are independent, but if any genealogy is traced far enough back in time, ancestors begin to appear on multiple lines of the genealogy, until eventually, a  population founder  appears on all lines of the genealogy.)


The X chromosome in humans spans more than 153 million  base pairs  (the building material of  DNA ). It represents about 800 protein-coding genes compared to the Y chromosome containing about 70 genes, out of 20,000–25,000 total genes in the human genome.
Each person usually has one pair of sex chromosomes in each cell. Females typically have two X chromosomes, whereas males typically have one X and one  Y chromosome . Both males and females retain one of their mother's X chromosomes, and females retain their second X chromosome from their father. Since the father retains his X chromosome from his mother, a human female has one X chromosome from her paternal grandmother (father's side), and one X chromosome from her mother. This inheritance pattern  follows the Fibonacci numbers  at a given ancestral depth. [ citation needed ]


Genetic disorders  that are due to  mutations  in genes on the X chromosome are described as  X linked . If the X chromosome has a genetic disease gene, it always causes illness in male patients, since men have only one X chromosome and therefore only one copy of each gene. Females, instead, require both X chromosomes to have the illness, and as a result could potentially only be a carrier of genetic illness, since their second X chromosome overrides the first. For example,  hemophilia A  and  B  and  congenital red–green color blindness  run in families this way.


The X chromosome carries hundreds of genes but few, if any, of these have anything to do directly with sex determination. Early in  embryonic  development in females, one of the two X chromosomes is permanently inactivated in nearly all somatic cells (cells other than  egg  and  sperm  cells). This phenomenon is called  X-inactivation  or  Lyonization , and creates a  Barr body . If X-inactivation in the somatic cell meant a complete de-functionalizing of one of the X-chromosomes, it would ensure that females, like males, had only one functional copy of the X chromosome in each somatic cell. This was previously assumed to be the case. However, recent research suggests that the  Barr body  may be more biologically active than was previously supposed. [ 8 ]


The partial  inactivation of the X-chromosome  is due to repressive  heterochromatin  that compacts the DNA and prevents the expression of most genes.  Heterochromatin compaction is regulated by Polycomb Repressive Complex 2 ( PRC2 ). [ 9 ]


The following are some of the gene count estimates of human X chromosome. Because researchers use different approaches to  genome annotation  their predictions of the  number of genes  on each chromosome varies (for technical details, see  gene prediction ). Among various projects, the collaborative consensus coding sequence project ( CCDS ) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes. [ 10 ]


The following is a partial list of genes on human chromosome X. For complete list, see the link in the infobox on the right.


It is theorized by Ross et al. 2005 and Ohno 1967 that the X chromosome is at least partially derived from the autosomal (non-sex-related) genome of other mammals, evidenced from interspecies genomic sequence alignments.


The X chromosome is notably larger and has a more active  euchromatin  region than its  Y chromosome  counterpart. Further comparison of the X and Y reveal regions of homology between the two. However, the corresponding region in the Y appears far shorter and lacks regions that are conserved in the X throughout primate species, implying a genetic degeneration for Y in that region. Because males have only one X chromosome, they are more likely to have an X chromosome-related disease.


It is estimated that about 10% of the genes encoded by the X chromosome are associated with a family of "CT" genes, so named because they encode for markers found in both tumor cells (in cancer patients) as well as in the human  testis  (in healthy patients). [ 18 ]


Klinefelter syndrome :


Trisomy X


Turner syndrome :


Sex linkage  was first discovered in insects, e.g.,  T. H. Morgan 's 1910 discovery of the pattern of inheritance of  the white eyes mutation in  Drosophila melanogaster . [ 23 ]   Such discoveries helped to explain x-linked disorders in humans, e.g.,  haemophilia  A and B,  adrenoleukodystrophy , and  red-green color blindness .


XX male syndrome  is a rare disorder, where the  SRY  region of the Y chromosome has recombined to be located on one of the X chromosomes. As a result, the XX combination after fertilization has the same effect as a XY combination, resulting in a male. However, the other genes of the X chromosome cause feminization as well.


X-linked endothelial corneal dystrophy  is an extremely rare disease of cornea associated with Xq25 region.  Lisch epithelial corneal dystrophy  is associated with Xp22.3.


Megalocornea 1  is associated with Xq21.3-q22 [ medical citation needed ]


Adrenoleukodystrophy , a rare and fatal disorder that is carried by the mother on the x-cell. It affects only boys between the ages of 5 and 10 and destroys the protective cell surrounding the nerves,  myelin , in the brain. The female carrier hardly shows any symptoms because females have a copy of the x-cell. This disorder causes a once healthy boy to lose all abilities to walk, talk, see, hear, and even swallow. Within 2 years after diagnosis, most boys with Adrenoleukodystrophy die.


In July 2020 scientists reported the first complete and gap-less  assembly  of a  human X chromosome . [ 32 ] [ 33 ]


The  Y chromosome  is one of two  sex chromosomes  in  therian mammals  and  other organisms . Along with the  X chromosome , it is part of the  XY sex-determination system , in which the Y is the  sex-determining  chromosome because the presence of the Y chromosome causes  offspring  produced in  sexual reproduction  to be of male  sex . In mammals, the Y chromosome contains the  SRY  gene, which triggers development of  male gonads . The Y chromosome is passed only from male parents to male offspring.


The Y chromosome was identified as a sex-determining chromosome by  Nettie Stevens  at  Bryn Mawr College  in 1905 during a study of the  mealworm   Tenebrio molitor .  Edmund Beecher Wilson  independently discovered the same mechanisms the same year, working with  Hemiptera . Stevens proposed that chromosomes always existed in pairs and that the smaller chromosome (now labelled "Y") was the pair of the X chromosome discovered in 1890 by  Hermann Henking . She realized that the previous idea of  Clarence Erwin McClung , that the X chromosome determines sex, was wrong and that  sex determination  is, in fact, due to the presence or absence of the Y chromosome. In the early 1920s,  Theophilus Painter  determined that X and Y chromosomes determined sex in humans (and other mammals). [ 4 ]


The chromosome was given the name "Y" simply to follow on from Henking's "X" alphabetically. [ 5 ] [ 6 ]  The idea that the Y chromosome was named after its similarity in appearance to the letter "Y" is mistaken. All chromosomes normally appear as an amorphous blob under the microscope and only take on a well-defined shape during  mitosis . This shape is vaguely X-shaped for all chromosomes. It is entirely coincidental that the Y chromosome, during  mitosis , has two very short branches which can look merged under the microscope and appear as the descender of a Y-shape. [ 5 ] : 65–66


Most therian mammals have only one pair of sex chromosomes in each cell. Males have one Y chromosome and one  X chromosome , while females have two X chromosomes. In mammals, the Y chromosome contains a gene,  SRY , which triggers embryonic development as a male. The Y chromosomes of humans and other mammals also contain other genes needed for normal sperm production. [ citation needed ]