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Lyonization vs Genetic Imprinting

Lyonization vs Genetic Imprinting



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Lyonization is the process in which there is inactivation of an X chromosome in females. This process is implicated in mosaic forms of turner's syndrome (in this case the alteredX chromosomeis Lyonised, thus allowing the normalX Chromosometo express itself).

  1. Is Lyonization considered as a form of genetic imprinting? What is the difference between the two (if no)?

  2. Lyonization is a random process (according to the extent of my knowledge whichX chromosomeis inactivated is not predicatable). Is genetic imprinting also random?

  3. Is there any known aberration of Lyonization in males? (meaning the singleX ChromosomeorY Chromosomegets silenced)


  1. I use the term "X-inactivation" instead of "lyonization". Anyway, X-inactivation is a very specific process by which an entire X chromosome (or equivalent sex chromosome) in a female mammal is completely silenced.

"Imprinting" is typically applied to single genes, wherein genes inherited from a specific parent are always epigenetically silenced. The genes are usually autosomal. Thus, we're talking about scales : entire sex chromosome composed of thousands of genes (x-inactivation) vs single genes (imprinting)

  1. The choice for which X-chromosome is inactivated is sporadic and different in different cells within the body. It is controlled by opposing expression of different non-coding RNAs (XIST on the inactive X and TSIX on the active X).

Imprinting is very specific to the allele that is inherited from a specific parent (for example, some genes are paternally imprinted, while others can be maternally imprinted).

  1. Males with aberrant X-inactivation will lack any expression of genes carried on their single X-chromosome, a condition that will not result in a viable fetus. However, whether there are aberrant X-inactivations in single cells or tissues of ageing adult males… perhaps likely yes, given all the other aberrant somatic mutation events that occur over the course of life.

I guess, we are talking about mammals here (because in other organisms leveling up of expression on sex chromosomes happens differently: e.g. in flies females express both X chromosomes, while fly males express their single X at twice as high level).

In embryo proper the decision of whether to inactivate maternal or paternal X seems to be at random. This inactivation adjusts level of expression of genes on X to be in the same ball park as on autosomes and in the same ballpark between males and females. Neither farther nor mother cares about which copy of X gets inactivated in individual cells of an embryo.

When we say that a gene is imprinted, that means only one copy of the gene is expressed but, to the contrary of what happens with X, maternal or paternal origin of the expressed copy is predetermined (so there is no randomness in which copy is inactive). Imprinting is usually a property of genes expressed during embryonic development and it is related to tug of war between farther and mother's interests: the farther "wants" embryo to take as much resources from the mother as possible (so paternal copies of some genes tend to be highly expressed), while mother wants not to give too much to one embryo, so that she can raise many more progeny (so maternal copies of some other genes tend to be highly expressed). This whole thing is interestingly described Matt Ridley book The Red Queen: Sex and the Evolution of Human Nature.

Note, that to confuse matters a little bit, in placenta of female embryos it is always the paternally inherted X that gets silenced, so the whole X chromosome is imprinted in extra-embryonic tissues of female embryos.

And in males X chromosomes do not get inactivated, since many genes are present solely on X chromosome and not on Y, so inactivating the only copy of X chromosome is lethal.


People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or “turned on,” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting.

In genes that undergo genomic imprinting, the parent of origin is often marked, or “stamped,” on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. These molecules identify which copy of a gene was inherited from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes.

Only a small percentage of all human genes undergo genomic imprinting. Researchers are not yet certain why some genes are imprinted and others are not. They do know that imprinted genes tend to cluster together in the same regions of chromosomes. Two major clusters of imprinted genes have been identified in humans, one on the short (p) arm of chromosome 11 (at position 11p15) and another on the long (q) arm of chromosome 15 (in the region 15q11 to 15q13).


What is X Inactivation?

X inactivation takes place in some females. It is the inactivation of one X chromosome, which becomes a transcriptionally inactive structure in X inactivation. Once this occurs, this X chromosome will remain inactive throughout the lifetime of the cell and its descendants in the organism. The inactivated X chromosome condenses into a compact structure called a Barr body, and it is stably maintained in a silent state.

Figure 01: X Inactivation

X inactivation process depends on the control of two non-coding complementary RNAs. Moreover, X inactivation can occur randomly or due to imprinting. In addition, X inactivation does not happen in males, who have only one X chromosome.


Genomic imprinting in plants-revisiting existing models

Genomic imprinting is an epigenetic phenomenon leading to parentally biased gene expression. Throughout the years, extensive efforts have been made to characterize the epigenetic marks underlying imprinting in animals and plants. As a result, DNA methylation asymmetries between parental genomes emerged as the primary factor controlling the imprinting status of many genes. Nevertheless, the data accumulated so far suggest that this process cannot solely explain the imprinting of all genes. In this review, we revisit the current models explaining imprinting regulation in plants, and discuss novel regulatory mechanisms that could function independently of parental DNA methylation asymmetries in the establishment of imprinting.

Keywords: DNA methylation Polycomb group proteins genomic imprinting plants.

© 2020 Batista and Köhler Published by Cold Spring Harbor Laboratory Press.

Figures

Expression of genes belonging to…

Expression of genes belonging to the main epigenetic pathways in the Arabidopsis female…

Models of imprinted gene regulation.…

Models of imprinted gene regulation. Different models for the epigenetic regulation of MEGs…


Discussion

The key result of our model is that natural selection favors the evolution of genomic imprinting, because it increases offspring fitness by enhancing the genetic integration of coadapted offspring and maternal traits. Our model provides a number of testable predictions, which, in conjunction with existing hypotheses, may yield a better understanding of the functional basis for the evolutionary origin of imprinting across the genome. First, central to our model is the prediction that in systems where selection favors coadaptation, the loci involved in the intimate maternal–offspring interaction are more likely to show patterns of imprinting with maternal expression. The predominance of maternally expressed genes in both placental [28] and early seed development [45] may thus be explained by our model. In the case of the placenta, the kinship hypothesis, the intralocus conflict hypothesis, and our coadaptation model predict imprinting to occur at different loci and/or at different stages of development, but only the coadaptation hypothesis makes the explicit prediction of the predominance of maternally expressed genes. Thus, the coadaptation hypothesis may explain the abundance of maternally expressed genes, especially at loci affecting traits that are vital for the development of a functional placenta, such as those expressed early in development or at the interface of the maternal–fetal interaction (e.g., at the boundary of the maternal and embryonic contributions to the placenta). By contrast, the kinship hypothesis may explain the occurrence of imprinting at loci that govern resource transfer between embryo and mother (e.g., Igf2 and Igf2r) [9], where an opportunity for conflict over optimal levels of maternal investment exists (with expression of maternally or paternally inherited alleles, depending on the effect of the locus). Finally, the intralocus sexual conflict hypothesis may explain the occurrence of imprinting at loci with alleles under differential directional selection in males and females, but therefore may not make any specific predictions regarding the pattern of imprinting in the placenta if differential selection does not occur at such an early stage of development.

Second, we expect the incidence of imprinting at loci affecting traits involved in maternal–offspring interactions to be higher in taxa in which such interactions have a greater impact on offspring fitness. Like the intralocus sexual conflict model, our results also suggest that imprinting may occur in systems that previously have not been the focus of research on genomic imprinting because they do not offer the opportunity for conflict over maternal investment, but in which coadapted maternal–offspring traits have potentially large fitness effects (e.g., systems where selection favors coadaptation of oviposition site preference and offspring performance, such as in many phytophagous insects [46]). Our model focuses on maternal–offspring interactions, but it would be interesting to investigate whether our predictions hold for systems in which the father is the primary caregiver, such as in several fish or arthropod species [47,48]. Given that the coadaptation of paternal and offspring traits has fitness consequences for offspring, we would expect expression of the paternal allele.

Finally, although we offer an alternate theory for the evolution of genomic imprinting, we stress that the diversity of imprinting patterns and associated phenotypic effects found across different genes suggests the possibility that imprinting may have evolved for different reasons in different taxa and loci [11,49]. This applies, in particular, to maternal–offspring interactions, in which some of the underlying genes may be involved in conflict over maternal provisioning while others might be expressed for their role in maternal–offspring coadaptation, either at different stages in development or in different tissues.

At present, most evidence in support of or against theories of imprinting comes from studies on phenotypic effects identified by gene targeting [6]. However, studying the effects of mutated genes may provide only limited insight into the evolutionary causes underlying imprinting at specific loci, because these neither necessarily reflect the evolutionarily important functions of the genes in question nor naturally occurring patterns of allelic variation at such loci. For example, mutating a gene that plays an important role in placental development might result in retarded (or perhaps enhanced) offspring growth, but the evolutionarily important effect of the gene may be proper development of a functional placenta rather than growth promoting or inhibition, per se. Thus, such a gene could have evolved maternal expression due to coadaptation of alleles that function together for proper placental development, whereas effects on growth in knock-out mutants may reflect pleiotropic outcomes of severe genetic perturbations. Experimental and comparative analyses designed to directly test alternative theories for the evolutionary origin of imprinting are required to elucidate the diversity of imprinting patterns at both the genomic and taxonomic level [50]. Such analyses might compare different species that show different patterns of maternal–offspring interaction and coadaptation to test whether loci involved in coadaptation or conflict show predicted patterns of imprinting. Likewise, analyses within species might examine the effects of allelic variation at loci showing maternal versus paternal expression to test whether such loci show patterns consistent with coadaptation. For such a test, one might examine whether the effects of imprinted loci with maternal expression depend on the genotype of the mother and whether the resulting pattern is consistent with selection for coadaptation. Thus, by offering a testable alternative in addition to existing hypotheses, our model allows a more comprehensive investigation of both the proximate function and the evolution of genomic imprinting.


What is the Difference Between Uniparental Disomy and Genomic Imprinting?

Uniparental disomy and genomic imprinting are two diverse concepts. Uniparental disomy involves only one parent organism, while genomic imprinting involves both parents. Uniparental disomy takes place at the point of meiosis forming the gametes. In contrast, genomic imprinting takes place in the offspring following fertilization process. So, this is the key difference between uniparental disomy and genomic imprinting.

The below infographic presents more information regarding the difference between uniparental disomy and genomic imprinting.


Three Examples

1. IGF2

In humans (and other mammals like mice and pigs) the IGF2 allele inherited from the father (paternal) is expressed the allele inherited from the mother is not.

If both alleles should begin to be expressed in a cell, that cell may develop into a cancer.

2. IGF2r

In mice the IGF2r allele inherited from the mother is expressed that from the father is not. Differential imprinting accounts for this, and the mechanism is described below.

3. XIST


The best-known form of imprinting is filial imprinting, in which a young animal narrows its social preferences to an object (typically a parent) as a result of exposure to that object. It is most obvious in nidifugous birds, which imprint on their parents and then follow them around. [1] It was first reported in domestic chickens, by Sir Thomas More in 1516 as described in his treatise Utopia, 350 years earlier than by the 19th-century amateur biologist Douglas Spalding. It was rediscovered by the early ethologist Oskar Heinroth, and studied extensively and popularized by his disciple Konrad Lorenz working with greylag geese. [2]

Lorenz demonstrated how incubator-hatched geese would imprint on the first suitable moving stimulus they saw within what he called a "critical period" between 13 and 16 hours shortly after hatching. For example, the goslings would imprint on Lorenz himself (to be more specific, on his wading boots), and he is often depicted being followed by a gaggle of geese who had imprinted on him. Lorenz also found that the geese could imprint on inanimate objects. In one notable experiment, they followed a box placed on a model train in circles around the track. [2] Filial imprinting is not restricted to non-human animals that are able to follow their parents, however.

The filial imprinting of birds was a primary technique used to create the movie Winged Migration (Le Peuple Migrateur), which contains a great deal of footage of migratory birds in flight. The birds imprinted on handlers, who wore yellow jackets and honked horns constantly. The birds were then trained to fly along with a variety of aircraft, primarily ultralights.

The Italian hang-glider pilot Angelo d'Arrigo extended this technique. D'Arrigo noted that the flight of a non-motorised hang-glider is very similar to the flight patterns of migratory birds both use updrafts of hot air (thermal currents) to gain altitude that then permits soaring flight over distance. He used this to reintroduce threatened species of raptors. [3] Because birds hatched in captivity have no mentor birds to teach them traditional migratory routes, D'Arrigo hatched chicks under the wing of his glider and they imprinted on him. Then, he taught the fledglings to fly and to hunt. The young birds followed him not only on the ground (as with Lorenz) but also in the air as he took the path of various migratory routes. He flew across the Sahara and over the Mediterranean Sea to Sicily with eagles, from Siberia to Iran (5,500 km) with a flock of Siberian cranes, and over Mount Everest with Nepalese eagles. In 2006, he worked with a condor in South America. [3]

In a similar project, orphaned Canada geese were trained to their normal migration route by the Canadian ultralight enthusiast Bill Lishman, as shown in the fact-based movie drama Fly Away Home.

Chicks of domestic chickens prefer to be near large groups of objects that they have imprinted on. This behaviour was used to determine that very young chicks of a few days old have rudimentary counting skills. In a series of experiments, they were made to imprint on plastic balls and could figure out which of two groups of balls hidden behind screens had the most balls. [4]

American coot mothers have the ability to recognize their chicks by imprinting on cues from the first chick that hatches. This allows mothers to distinguish their chicks from parasitic chicks.

The peregrine falcon has also been known to imprint on specific structures for their breeding grounds such as cliff sides and bridges and thus will favour that location for breeding. [5]

Sexual imprinting is the process by which a young animal learns the characteristics of a desirable mate. For example, male zebra finches appear to prefer mates with the appearance of the female bird that rears them, rather than that of the birth parent when they are different. [6]

Sexual attraction to humans can develop in non-human mammals or birds as a result of sexual imprinting when reared from young by humans. One example is London Zoo female giant panda Chi Chi. When taken to Moscow Zoo for mating with the male giant panda An An, she refused his attempts to mate with her, but made a full sexual self-presentation to a zookeeper. [7] [8]

It commonly occurs in falconry birds reared from hatching by humans. Such birds are called "imprints" in falconry. When an imprint must be bred from, the breeder lets the male bird copulate with their head while they are wearing a special hat with pockets on to catch the male bird's semen. The breeder then courts a suitable imprint female bird (including offering food, if it is part of that species's normal courtship). At "copulation", the breeder puts the flat of one hand on the female bird's back to represent the weight of a male bird, and with the other hand uses a pipette, or a hypodermic syringe without a needle, to squirt the semen into the female's cloaca. [9] [10]

Sexual imprinting on inanimate objects is a popular theory concerning the development of sexual fetishism. [11] For example, according to this theory, imprinting on shoes or boots (as with Konrad Lorenz's geese) would be the cause of shoe fetishism. [ citation needed ]

Some suggest that prenatal, perinatal and post-natal experiences leave imprints upon the limbic system, causing lifelong effects and this process is identified as limbic imprinting. [12] The term is also described as the human emotional map, deep-seated beliefs, and values that are stored in the brain's limbic system and govern people's lives at the subconscious level. [13] It is one of the suggested explanations for the claim that the experiences of an infant, particularly during the first two years of his life, contribute to his lifelong psychological development. [14] Imprinted genes can have astounding effects on body size, brain size, and the process in which the brain organizes its processes. Evolutionary trends within the animal kingdom have been shown to show substantive increase in the fore-brain particularly towards the limbic system, this evolution has even been thought of to have a mutative effect on the brain size trickling down the human ancestry. [15]

Reverse sexual imprinting is also seen in instances where two people who live in domestic proximity during the first few years in the life of either one become desensitized to later close sexual attraction. This phenomenon, known as the Westermarck effect, was first formally described by Finnish anthropologist Edvard Westermarck in his book The History of Human Marriage (1891). The Westermarck effect has since been observed in many places and cultures, including in the Israeli kibbutz system, and the Chinese shim-pua marriage customs, as well as in biological-related families.

In the case of the Israeli kibbutzim (collective farms), children were reared somewhat communally in peer groups, based on age, not biological relation. A study of the marriage patterns of these children later in life revealed that out of the nearly 3,000 marriages that occurred across the kibbutz system, only fourteen were between children from the same peer group. Of those fourteen, none had been reared together during the first six years of life. This result provides evidence not only that the Westermarck effect is demonstrable but that it operates during the period from birth to the age of six. [16] However, Eran Shor and Dalit Simchai claimed that the case of the kibbutzim actually provides little support for the Westermarck effect. [17]

When proximity during this critical period does not occur—for example, where a brother and sister are brought up separately, never meeting one another—they may find one another highly sexually attractive when they meet as adults. [18] This phenomenon is known as genetic sexual attraction. This observation supports the hypothesis that the Westermarck effect evolved because it suppressed inbreeding. This attraction may also be seen with cousin couples.

Sigmund Freud argued that as children, members of the same family naturally lust for one another, making it necessary for societies to create incest taboos, [19] but Westermarck argued the reverse, that the taboos themselves arise naturally as products of innate attitudes. Steven Pinker has written that Freud's conception of an urge to incest may have derived from Freud's own erotic reaction to his mother as a boy (attested in Freud's own writings), and speculates that Freud's reaction may have been due to lack of intimacy with his mother in early childhood, as Freud was wet-nursed. [20]

In human–computer interaction, baby duck syndrome denotes the tendency for computer users to "imprint" on the first system they learn, then judge other systems by their similarity to that first system. The result is that "users generally prefer systems similar to those they learned on and dislike unfamiliar systems". [21] The issue may present itself relatively early in a computer user's experience, and it has been observed to impede education of students in new software systems or user interfaces. [22]


Narration

Genetic imprinting is a rather mysterious phenomenon which has become somewhat better understood in the last few years. Essentially, what it refers to is the chemical modification of a DNA sequence. Keep in mind here that the DNA sequence itself is not changing. These are modifications to the DNA sequence itself that occur in a cell--usually refers to a germ cell, either an egg cell or a sperm cell--and that change is passed on from one generation to another. The reason it confused scientists for many years is that it is a non-sequenced-based mechanism of inheritance. Initially, it was thought that all inheritance is based on changes in sequence this turns out not to be true. In one of those mechanisms, which is not involved in change of sequence, but rather an inherited chemical change to a DNA sequence, is referred to as imprinting. And that imprinting, the reason it's important is that chemical modification, which is passed on from the mother or the father to the offspring, changes the function of the gene or the gene product, whether it's expression or actually the function of the gene product itself.


The influence of mom and dad

The epigenetics of parental care got its start some two decades ago when Michael Meaney and his colleagues showed that rats' mothering styles influenced their pups' response to stress as adults as a result of effects on the glucocorticoid receptor in the hippocampus. Offspring of nurturing mothers tended to be less anxious than those of more lackadaisical mothers. The Montreal researchers showed how early experience could shape an adult animal's behavior and even disease susceptibility, and they attributed these findings to gene changes wrought by epigenetic events.

Environmental chemicals can also affect parenting and offspring behavior. Many studies have been done on the ubiquitous endocrine disrupter bisphenol A, which alters DNA methylation. It has a great many effects in rats and mice treated during gestation, both on recipients and on their offspring. Learning, memory, and behavior, including maternal behavior, seem particularly affected. For example: Treated moms do less licking and grooming of their pups, and the pups tend to explore less and behave more anxiously, avoiding new places.

Researchers in Frances Champagne's lab at Columbia University in New York City are comparing social enrichment with social isolation or social impoverishment in rodents soon after their births, examining how those different environments change genes that govern social and reproductive behavior. Champagne's is among several labs to show that social experiences—in particular, social experiences that are relevant to mammalian development—can induce epigenetic changes. These researchers are studying not just extremes of maternal care, but also how natural variation in mothering styles can induce significant differences in epigenetic profiles.

Their latest work defines the outcomes of communal rearing in mice. Communal rearing, which comes naturally to mice but is not found often in the lab, induces multiple changes in both the brain and behavior that persist across generations, even in those offspring who were not reared in a communal nest.

There has been a big increase in research on fathers' experiences and how those are transmitted to offspring, Champagne says. Paternal effects may be particularly helpful in sorting out confounding factors in epigenetic studies, because what fathers transmit to offspring biology is only through sperm and whatever epigenetic marks they retain. There is no cytoplasm, no mitochondria, no uterus, and no messy maternal behavior to complicate interpretation. “It's a way of actually seeing whether there's some sort of germ cell epigenetic change,” she says.

Subjecting male lab animals to endocrine-disrupting chemicals and other toxins has produced behavioral effects in their offspring, even when the exposure takes place well before mating. When male mice and rats are exposed to alcohol before mating, their offspring do less well at discrimination on spatial tasks, and they are more aggressive, take more risks, and display more anxiety-like behavior than offspring of unexposed animals. Males exposed to cocaine have offspring with smaller brains and deficits in attention and working memory. Even males exposed to toxins during their own embryonic development transmit detrimental effects to their offspring. In all of the examples mentioned here, epigenetic changes, especially those in DNA methylation, have been observed.


Pediatric Germ Cell Tumors

A. Lindsay Frazier , James F. Amatruda , in Oncology of Infancy and Childhood , 2009

Malignant Germ Cell Tumors of Infants and Children

The genomic aberrations seen in malignant GCTs of infants and children are generally distinct from those occurring in postpubertal tumors. 19,61,158,208,294 Pediatric germ cell tumors show only partial erasure of parental imprinting, 103,105,127,158,296,343,344 indicating that prepubertal GCTs likely arise from an earlier stage of embryonic germ cell development than postpubertal tumors. A similar pattern of imprinting is seen in gonadal and extragonadal pediatric GCTs, suggesting that gonadal and nongonadal tumors share a common pathogenesis and cell of origin. 103,105,158,296,344

In analyses of chromosomal structure and copy number imbalances, differences between the pediatric and adolescent and adult GCTs are again consistently found. In the prepubertal period, pure teratomas of the testis or of extragonadal sites almost always exhibit a normal profile in genomic analyses, including classic cytogenetics, fluorescence in situ hybridization, loss of heterozygosity analysis, and array comparative genomic hybridization (CGH). 127,138,157,209,345-347 These data contrast sharply with the universally abnormal cytogenetic profile of postpubertal teratomas arising as a component of a mixed malignant germ cell tumor. In adolescents and adult germ cell tumors, only mature teratomas of the ovary and dermoid and epidermoid cysts of the testis exhibit normal cytogenetics, suggesting that these tumors may share a common pathogenesis with prepubertal teratomas. 127,137

In children younger than 5 years, yolk sac tumor is the most common malignant germ cell tumor of the testis and of extragonadal sites. Unlike teratomas, cytogenetic and other genomic aberrations are consistently reported in analyses of yolk sac tumors in infants and children. The most common imbalances reported are gains at chromosomes 1p and 20q and losses at chromosome 1p and chromosome 6q. 103,138,139,158,294,295,346-350 More recently, the advent of higher resolution techniques, such as array-based CGH, has further defined chromosomal aberrations in this group of tumors. Veltman and coworkers 209 have reported the array-based CGH profiles of a series of 24 germ cell tumors from patients younger than 5 years, including 16 teratomas and 8 yolk sac tumors. Most of the teratomas had normal CGH profiles, with two teratomas exhibiting loss of chromosome 20p as the only recurrent change. In contrast, all the yolk sac tumors had abnormal profiles. The recurrent changes, seen in at least three of the eight yolk sac tumors, included gains of chromosomes 1q (1q32-1qter), 3p (3p21-pter), and 20q (20q13), and loss of chromosomes 1p (1p35-pter), 6q (6q24-qter), and 18q (18q21-qter). In their study, only one tumor from a child younger than 5 years exhibited gain of chromosome 12p, whereas five of seven cases from children older than 5 years showed gains at chromosome 12 p. Most of these tumors occurred in the ovary, supporting the hypothesis that ovarian and testicular malignant GCTs have a common pathogenesis, at least in older children and adults. 1,351 Recently, a larger study from the British Children's Cancer and Leukaemia Group examined the metaphase CGH profile of 34 malignant germ cell tumors in children younger than 16 years ( Fig. 23-13 ). 352 This study supported the previous reports of an increased frequency of loss of chromosomes 1p and 6q and gain of chromosome 3p in yolk sac tumors. Intriguingly, 4 of 14 malignant GCTs from children younger than 5 years demonstrated gain of 12p, including gain of the 12p11 locus that is strongly associated with adolescent and adult malignant GCTs in two cases. Therefore, childhood and adolescent and adult malignant GCTs may share more pathogenic mechanisms in common than was previously appreciated, based on the analysis of a relatively small number of cases.

Loss of chromosomes 1p and 6q correlates with loss of heterozygosity analysis, indicating true allelic loss in these regions in pediatric GCTs. 347,353 However, the most common chromosomal aberrations of pediatric GCTs—1p−, 1q+, 6q−, and 20q+—are not highly specific for GCTs, but are seen in other cancers of childhood, including neuroblastoma and Wilms' tumor, as well as carcinomas. 354,355 Deletion of chromosome 1p is associated with MYCN amplification and poor prognosis in neuroblastoma, 356,357 which has led to the speculation that one or more genes in this interval may act as a tumor suppressor in neuroblastoma. 358 Several candidate genes have been proposed, including CHD5, TNFRSF25, CAMTA1, and AJAP1. 359 CHD5 was recently shown to act as a tumor suppressor in vivo. 71 Whether these or other genes in the 1p and 6q deleted regions play a pathogenic role in pediatric malignant GCTs is not currently known.