Why are mice with a single X chromosome and no Y chromosome males?

Why are mice with a single X chromosome and no Y chromosome males?

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I was searching online and I read this article Mice can be male without Y chromosome and this is a part of it:

The experiments demonstrate that there are multiple ways to make males, says Richard Behringer, a developmental geneticist at MD Anderson Cancer Center in Houston. “They've done it without any Y chromosome gene information,” he says. “There's not even a sniff of the Y around.”

I know that mouses are separated to males and females, and they both necessary for reproduction. Can someone please explain to me how could this possibly be? there's a lot of biology specific terms that i did not understand well

Almost all mammals (including mice and humans) have two sexes where the males have a Y chromosome and an X chromosome (whereas females have two X and no Y chromosomes). This is not the only way organisms can determine sexes, but it's the way mammals evolved to do it.

So how does having a Y cause an individual to be male? The Y has only a few genes (less than all other chromosomes), but it has genes that occur only on the Y. One of these in particular, the one called SRY, is the main gene that causes the individual to develop male characteristics. It mostly does its job indirectly, by making a protein that affects many other genes on other chromosomes that in turn do the work of building and maintaining the male form.

In the experiments reported by the article mentioned in the question, they managed to cause mice without a Y chromosome to develop many male characteristics. They did this by faking one or two of the actions of SRY. One of the many actions of SRY is to turn on a gene called Sox9 (which is on a non-Y chromosome), and it turns out Sox9 causes most of the things that make the male mouse form.

So the experimenters found a way to turn on Sox9 without using SRY or anything else from a Y chromosome. This got them mice that looked male, but didn't produce sperm. So they did something further that substituted for a Y chromosome, and caused a weak gene on the X to work at many-times strength to do the job that a strong Y gene normally does. This caused the special "male" mice to produce sperm. But these sperm were not fully functional (they couldn't swim and enter the egg), so they showed they were essentially sperm by simply using a tiny needle to inject the semi-functional sperm into mouse eggs and have those eggs develop into viable baby mice.

Bottom line, if you use artificial methods to do what the Y chromosome does, you can make male mice which do not have a Y chromosome (and learn some things in the process).

The bull Y chromosome has evolved to bully its way into gametes

Researchers at Whitehead Institute have sequenced the Y chromosome of a Hereford bull. Credit: Richard Webb / Hereford bull calf / CC BY-SA 2.0

In a new study, published Nov. 18 in the journal Genome Research, scientists in the lab of Whitehead Institute Member David Page present the first ever full, high-resolution sequence of the Y chromosome of a Hereford bull. The research, more than a decade in the making, suggests that bulls' Y chromosomes have evolved dozens of copies of the same genes in a selfish attempt to make more males—a move that is countered in the female-determining X chromosome.

"When you have an X and a Y chromosome, it's a setup for conflict," said Page, who is also a professor of biology at the Massachusetts Institute of Technology and investigator with the Howard Hughes Medical Institute. "Seeing this full blown competition between the cattle X and Y means we have to think more deeply about this conflict as a constant and general feature of sex chromosomes in mammals."

This insight into the forces that govern sex chromosome behavior and evolution will help scientists in Page's lab study genetic differences between males and females and how they play out in health and disease across every part of the body, Page added.

Of mice, men and cattle

Sex chromosomes—the X and the Y—evolved from a regular pair of symmetrical chromosomes some 200 million years ago. Those born biologically female have two X chromosomes. Those born biologically male have one X and one Y.

Page's lab successfully sequenced the human Y chromosome in 2003, and afterwards the researchers wanted to be able to compare the sequence to its counterparts in other animals in order to help understand how they have evolved and diverged over time.

To make these comparisons, researchers in Page's lab laid out a list of several mammals—including chimps, opossums, and mice—that occupied different branches of the mammalian family tree. One after another, the scientists began sequencing these creatures' Ys, using a high-resolution sequencing method called SHIMS—short for Single-Haplotype Iterative Mapping and Sequencing—to obtain a level of detail that other techniques, like shotgun sequencing, can't.

This powerful sequencing technology allowed the researchers to observe a strange peculiarity of Y chromosomes: in some species, nearly all of the genetic material on the Y is made up of sequences of DNA that have been amplified dozens or hundreds of times over—"like a hall of mirrors," Page said.

In mice, for example, repeats of just a few testis-specific genes make up nearly 98 percent of the Y chromosome. In humans, however, repeats make up only about 45 percent. "We wanted to know if this was just a peculiarity of rodents, or if other Y chromosomes might come close," Page said.

That's where the bull came in. "Outside of primates and rodents, the next branch off the mammalian tree includes bull," said Jennifer Hughes, a researcher in Page's lab and the first author of the paper. "We didn't know if the bull's Y chromosome would look like a mouse Y or a human Y or something else entirely."

The running of the bull's (sequencing data)

It took the Page Lab and collaborators at Baylor College of Medicine's Human Genome Sequencing Center, the McDonnell Genome Institute at Washington University, Texas A&M University, and other institutions more than a decade to tease apart the complexities of the bull Y chromosome. In fact, it turned out to be the most gene-dense of any Y chromosome ever mapped—largely due to the fact that 96 percent of its genetic material was made up of repetitive sequences.

As in the mouse, most of the bull's "hall of mirrors" repeats appeared to be expressed in the testis. But the question remained: Why? "What drives it can't just be purely making more sperm, because that's just overkill, right?" Hughes said. "You don't really need hundreds of copies of a gene to accomplish that task."

The researchers found a clue when they took a closer look at the bovine X chromosome: the female-determining sex chromosome also had a few copies of these testis-specific genes. "We don't really know the mechanism in the bull, but the thought is that somehow the amplification of these genes in the Y has to do with helping the Y get passed on—and the X copies are amplified to compete against that tendency and help the X," Hughes said.

This X-Y arms race has been proven to happen in mice: somehow, repetitive genes on the Y chromosome give it an extra edge when it comes to ending up in the sperm during gamete formation. In a 2012 study, researchers knocked out the Y-chromosome repeats. Without the extra genes, more X chromosomes than Ys ended up in sperm cells, and the sex ratio of offspring skewed female. Over years of evolution, the X has developed repeats as well—its own way to get a leg up in the race.

Competition between X and Y chromosomes is selfish, Hughes said, because it's not a good thing for the species to have a skewed sex ratio. Thus, these alterations benefit only the lucky chromosome that ends up in the fertilized egg. The fact that a selfish—and even detrimental—mechanism would continue for millions of years in disparate branches of the evolutionary tree suggests that these conflicts may be an inevitable side effect of having a pair of asymmetrical sex chromosomes. "These X-Y arms races have probably been around for as long as mammals have been around," Page said.

Evolutionary theory aside, knowing the mechanisms controlling the sex ratios of cattle could be of practical use in the coming years. "It could be of great interest to breeders, because they would love to be able to manipulate the sex of cattle offspring," Hughes said. "For example, dairy farmers would prefer more females and meat farmers would prefer more males."

Right now, the lab is working on leafing out the branches of their Y chromosome evolutionary tree. The bull's is the seventh sex chromosome to be completely sequenced using the SHIMS method. Hughes, Page and the lab are also eyeing members of other animal groups, including reptiles.

"Our lab is focused on sex differences across the human body, and all of that work really is inspired by lessons that we've learned by comparing the Y chromosomes of different animals with our own," Page said. "It's like when you go to an art gallery and just sit on a bench and look and feel inspired—these sequences are an infinite source of inspiration in the work we are doing. And we can now add the bull to our gallery."

These Little Creatures Have The 'Weirdest Sex Chromosome System Known to Science'

When it comes to dividing animals along sex lines, evolution is known for getting creative. The chromosomes that determine baby-making functions have been reinvented so often throughout the ages, it's hard to keep track.

Some groups, like mammals, are thought to be fairly consistent in how they genetically cast lots in the game of reproduction. But creeping voles (Microtus oregoni) clearly didn't get that memo.

Now, US researchers have a better idea of just what's going on with the tiny oddball.

Fifty years ago, Japanese American evolutionary biologist Susumu Ohno pointed out some of the stranger features of how sex chromosomes are distributed in this adorable little North American rodent.

For example, while most placental and marsupial mammals have two X chromosomes in most of their cells, female creeping voles have just the one. Confusingly, where our sex cells halve their chromosome numbers, inside the tissues that produce ova in creeping voles you'll find a double-X arrangement.

The males, at least according to Ohno, are more like typical mammals with an X and Y in each of the body's non-sex cells and a single chromosome in the cell lines that give rise to sperm. Only for some reason it's always the same 'Y' chromosome.

Closely related voles don't show these characteristics, so whatever happened to the creeping vole, it had to have taken place within the past couple of million years.

It's been a puzzle begging to be solved, so biologist Scott Roy and his colleagues decided it was high time to investigate the creeping vole's genes, to work out just what made them so freaky.

"This is basically the weirdest sex chromosome system known to science," says Roy.

What they uncovered is even stranger than Ohno would have ever imagined.

Starting with the male, Roy and his team used cutting edge genetic sequencing technology to come up with scaffolds representing complete chromosomes.

They also used RNA sequencing to get a sense of what all of the genes were making in both the male and female voles, and compared this with similar transcript libraries taken from females of the related prairie vole (M. ochrogaster).

All of this revealed that there was no Y chromosome, at least in a form we might find in other mammals, such as rats and mice. What Ohno had labelled a Y chromosome turned out to be a fusion of ancestral X and a small handful of Y sequences.

On closer inspection of the female's X chromosome, the team found it was also a chimera of old genes, some of which included ancestral Y genes. These were now only expressed in female creeping voles.

That all adds up to a sex determination system made entirely of two X chromosomes, distinguished only by a small selection of old Y-genes. How females avoid becoming males, especially with the crucial sex-determining region Y (SRY) gene located on their X chromosome, just introduces further mystery.

It's all rather topsy-turvy, not to mention completely unexpected.

"Mammals, with few exceptions, are kind of boring," says Roy.

"Previously we would have thought something like this is impossible."

Although the research reveals important details on the chromosomal mash-up that help explain how it might have happened, biologists are still a long way from working out the evolutionary forces that nudged the vole down this path.

It's clear the poor old Y chromosome tends to be a delicate flower that evolution has no problem stripping down from time to time, including in our own species. Future studies on the vole's branch of the family tree might even reveal a few truths on our own fate.

One thing is for sure – when it comes to splitting up the sexes, evolution is quite happy to throw out the rule book.

Sex chromosome dosage compensation

In mammals sex is determined by the presence or absence of a Y chromosome. Whereas females normally have two X chromosomes, males have an X and Y chromosome. Because of the imbalance in the number of chromosomes between males and females, mechanisms of dosage compensation have evolved. Dosage compensation is achieved in a two-fold manner in mammals (1) by inactivation of one of the two X chromosomes in females 23 and (2) upregulation of X-linked genes to balance the expression levels between X-linked and autosomal genes 24-28.

Female cells undergo a process of random X-inactivation so that approximately half of the cells have an inactive X M and half an inactive X P . The process of X chromosome inactivation is largely mediated by the expression of the long non-coding RNA Xist 29, 30, which acts to recruit repressive complexes silencing one X chromosome 31. DNA methylation is then necessary to maintain the silenced X chromosome 32, 33.

Despite being on the inactive X, many genes remain active. In humans,

15% of genes on the X chromosome escape X-inactivation, whereas in mice only

3-6% escape 5, 34, 35. Some of these escape genes have a Y chromosome paralog, resulting in equal expression from both sexes, and homologous pairing during meiosis. These regions of homology between the sex chromosomes are known as pseudoautosomal regions (PAR) 36. Other escape genes are expressed exclusively from the X chromosome, exhibiting higher expression in females 5, 34, 35. Therefore, in TS patients, who only have one X chromosome, transcription of a number of genes is lower as compared to normal females. Conversely, in KS patients, who have two X and one Y chromosomes, transcription of genes in the PAR is greater than in normal males. Some of these genes have been directly correlated to specific disease characteristics. For example, haploinsufficiency of SHOX (short stature homeobox-containing gene) contributes to the short stature of TS females 37, however, overexpression of SHOX in KS males is associated with taller height 38.

In addition to X-inactivation, a second form of dosage compensation maintains a balance between X-linked and autosomal gene expression by doubling transcription from the active X chromosome 24-28. Whereas little is known about the mechanisms coordinating upregulation of the X chromosome in mammals, this concept has been well documented in Drosophila. Similar to humans, Drosophila males and females are distinguished by their XY or XX karyotypes, respectively. In contrast to mammals, Drosophila males upregulate expression of their single X chromosome, and females maintain two active X chromosomes. In male somatic cells of Drosophila the male-specific lethal (MSL) complex, which is comprised of proteins and non-coding RNAs, is targeted to the X chromosome and is necessary for transcriptional upregulation. Importantly, the component males absent on the first (MOF) specifically acetylates histone H4 lysine 16 leading to opening of chromatin and increased expression 39. Although further research is essential to elucidate the mechanisms of X-upregulation in mammals, insights from Drosophila can help in understanding the mammalian system. In fact, many of the MSL components have orthologues in humans, and MOF containing complexes are largely evolutionarily conserved 40.

The demise of men? Nah

As we argue in a chapter in a new e-book, even if the Y chromosome in humans does disappear, it does not necessarily mean that males themselves are on their way out. Even in the species that have actually lost their Y chromosomes completely, males and females are both still necessary for reproduction.

In these cases, the SRY “master switch” gene that determines genetic maleness has moved to a different chromosome, meaning that these species produce males without needing a Y chromosome. However, the new sex-determining chromosome—the one that SRY moves on to—should then start the process of degeneration all over again due to the same lack of recombination that doomed their previous Y chromosome.

However, the interesting thing about humans is that while the Y chromosome is needed for normal human reproduction, many of the genes it carries are not necessary if you use assisted reproduction techniques. This means that genetic engineering may soon be able to replace the gene function of the Y chromosome, allowing same-sex female couples or infertile men to conceive. However, even if it became possible for everybody to conceive in this way, it seems highly unlikely that fertile humans would just stop reproducing naturally.

Although this is an interesting and hotly debated area of genetic research, there is little need to worry. We don’t even know whether the Y chromosome will disappear at all. And, as we’ve shown, even if it does, we will most likely continue to need men so that normal reproduction can continue.

Indeed, the prospect of a “farm animal” type system where a few “lucky” males are selected to father the majority of our children is certainly not on the horizon. In any event, there will be far more pressing concerns over the next 4.6m years.

Darren Griffin, Professor of Genetics, University of Kent

Peter Ellis, Lecturer in Molecular Biology and Reproduction, University of Kent

The Y chromosome is disappearing: What will happen to men?

Mole voles have no Y chromosomes. Credit: wikipedia

The Y chromosome may be a symbol of masculinity, but it is becoming increasingly clear that it is anything but strong and enduring. Although it carries the "master switch" gene, SRY, that determines whether an embryo will develop as male (XY) or female (XX), it contains very few other genes and is the only chromosome not necessary for life. Women, after all, manage just fine without one.

What's more, the Y chromosome has degenerated rapidly, leaving females with two perfectly normal X chromosomes, but males with an X and a shriveled Y. If the same rate of degeneration continues, the Y chromosome has just 4.6m years left before it disappears completely. This may sound like a long time, but it isn't when you consider that life has existed on Earth for 3.5 billion years.

The Y chromosome hasn't always been like this. If we rewind the clock to 166m years ago, to the very first mammals, the story was completely different. The early "proto-Y" chromosome was originally the same size as the X chromosome and contained all the same genes. However, Y chromosomes have a fundamental flaw. Unlike all other chromosomes, which we have two copies of in each of our cells, Y chromosomes are only ever present as a single copy, passed from fathers to their sons.

This means that genes on the Y chromosome cannot undergo genetic recombination, the "shuffling" of genes that occurs in each generation which helps to eliminate damaging gene mutations. Deprived of the benefits of recombination, Y chromosomal genes degenerate over time and are eventually lost from the genome.

Despite this, recent research has shown that the Y chromosome has developed some pretty convincing mechanisms to "put the brakes on," slowing the rate of gene loss to a possible standstill.

For example, a recent Danish study, published in PLoS Genetics, sequenced portions of the Y chromosome from 62 different men and found that it is prone to large scale structural rearrangements allowing "gene amplification"—the acquisition of multiple copies of genes that promote healthy sperm function and mitigate gene loss.

The study also showed that the Y chromosome has developed unusual structures called "palindromes" (DNA sequences that read the same forwards as backwards—like the word "kayak"), which protect it from further degradation. They recorded a high rate of "gene conversion events" within the palindromic sequences on the Y chromosome—this is basically a "copy and paste" process that allows damaged genes to be repaired using an undamaged back-up copy as a template.

Looking to other species (Y chromosomes exist in mammals and some other species), a growing body of evidence indicates that Y-chromosome gene amplification is a general principle across the board. These amplified genes play critical roles in sperm production and (at least in rodents) in regulating offspring sex ratio. Writing in Molecular Biology and Evolution recently, researchers give evidence that this increase in gene copy number in mice is a result of natural selection.

Chromosome Y in red, next to the much larger X chromosome. Credit: National Human Genome Research Institute

On the question of whether the Y chromosome will actually disappear, the scientific community, like the UK at the moment, is currently divided into the "leavers" and the "remainers." The latter group argues that its defense mechanisms do a great job and have rescued the Y chromosome. But the leavers say that all they are doing is allowing the Y chromosome to cling on by its fingernails, before eventually dropping off the cliff. The debate therefore continues.

A leading proponent of the leave argument, Jenny Graves from La Trobe University in Australia, claims that, if you take a long-term perspective, the Y chromosomes are inevitably doomed—even if they sometimes hold on a bit longer than expected. In a 2016 paper, she points out that Japanese spiny rats and mole voles have lost their Y chromosomes entirely—and argues that the processes of genes being lost or created on the Y chromosome inevitably lead to fertility problems. This in turn can ultimately drive the formation of entirely new species.

As argued in a chapter in a new e-book, even if the Y chromosome in humans does disappear, it does not necessarily mean that males themselves are on their way out. Even in the species that have actually lost their Y chromosomes completely, males and females are both still necessary for reproduction.

In these cases, the SRY "master switch" gene that determines genetic maleness has moved to a different chromosome, meaning that these species produce males without needing a Y chromosome. However, the new sex-determining chromosome—the one that SRY moves on to—should then start the process of degeneration all over again due to the same lack of recombination that doomed their previous Y chromosome.

The interesting thing about humans is that while the Y chromosome is needed for normal human reproduction, many of the genes it carries are not necessary if you use assisted reproduction techniques. This means that genetic engineering may soon be able to replace the gene function of the Y chromosome, allowing same-sex female couples or infertile men to conceive. However, even if it became possible for everybody to conceive in this way, it seems highly unlikely that fertile humans would just stop reproducing naturally.

Although this is an interesting and hotly debated area of genetic research, there is little need to worry. Scientists don't even know whether the Y chromosome will disappear at all. And, as shown, even if it does, we will most likely continue to need men so that normal reproduction can continue.

Indeed, the prospect of a "farm animal" type system where a few "lucky" males are selected to father the majority of our children is certainly not on the horizon. In any event, there will be far more pressing concerns over the next 4.6m years.

Single mutation leads to big effects in autism-related gene

NIH study provides insight into one mechanism underlying the higher prevalence of males in some cases of autism.

New findings suggest that a single mutation may contribute to increased prevalence of autism in boys than in girls. Roche Lab/NINDS

A new study in Neuron offers clues to why autism spectrum disorder (ASD) is more common in boys than in girls. National Institutes of Health scientists found that a single amino acid change in the NLGN4 gene, which has been linked to autism symptoms, may drive this difference in some cases. The study was conducted at NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

Researchers led by Katherine Roche, Ph.D., a neuroscientist at NINDS, compared two NLGN4 genes, (one on the X chromosome and one on the Y chromosome), which are important for establishing and maintaining synapses, the communication points between neurons.

Every cell in our body contains two sex chromosomes. Females have two X chromosomes males have one X and one Y chromosome. Until now, it was assumed that the NLGN4X and NLGN4Y genes, which encode proteins that are 97% identical, functioned equally well in neurons.

But using a variety of advanced technology including biochemistry, molecular biology, and imaging tools, Dr. Roche and her colleagues discovered that the proteins encoded by these genes display different functions. The NLGN4Y protein is less able to move to the cell surface in brain cells and is therefore unable to assemble and maintain synapses, making it difficult for neurons to send signals to one another. When the researchers fixed the error in cells in a dish, they restored much of its correct function.

“We really need to look at NLGN4X and NLGN4Y more carefully,” said Thien A. Nguyen, Ph.D., first author of the study and former graduate student in Dr. Roche’s lab. “Mutations in NLGN4X can lead to widespread and potentially very severe effects in brain function, and the role of NLGNY is still unclear.”

Dr. Roche’s team found that the problems with NLGN4Y were due to a single amino acid. The researchers also discovered that the region surrounding that amino acid in NLGN4X is sensitive to mutations in the human population. There are a cluster of variants found in this region in people with ASD and intellectual disability and these mutations result in a deficit in function for NLGN4X that is indistinguishable from NLGN4Y.

In females, when one of the NLGN4X genes has a mutation, the other one can often compensate. However, in males, diseases can occur when there is a mutation in NLGN4X because there is no compensation from NLGN4Y.

The current study suggests that if there is a mutation in NLGN4X, NLGN4Y is not able to take over, because it is a functionally different protein. If the mutations occur in regions of NLGN4X that affect the protein levels, that may result in autism-related symptoms including intellectual deficits. The inability of NLGN4Y to compensate for mutations in NLGN4X may help explain why males, who only have one X chromosome, tend to have a greater incidence of NLGN4X-associated ASD than females.

“The knowledge about these proteins will help doctors treating patients with mutations in NLGN4X better understand their symptoms,” said Dr. Roche.

This work was supported by the NIH Intramural Research Program.

The NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

NIH&hellipTurning Discovery Into Health ®


TA Nguyen et al. A cluster of autism-associated variants on X-linked NLGN4X functionally resemble NLGN4Y. Neuron. April 2, 2020.

Are YY chromosomes possible?

The Y chromosome is present only in males. It performs a significant function for developing male phenotypes, male secondary sexual characters and regulates gene expression of genes located on the Y chromosome.

Genes and sequences like SRY and TFD regions, respectively, are very very crucial factors for the development of male gonads as they participate in varieties of reproductive differentiation and determination activities.

Dysregulation of the SRY gene or abnormalities in TDF regions or AZF regions causes serious problems related to male sexuality. Infertility is a common cause of it.

The Y chromosomes possess less genetic content and so fewer genes. But are tightly regulated. Only a single copy of genes (on a single Y chromosome) is sufficient to perform all these functions explained above.

Now coming to the question what happens when another Y chromosome is present?

In normal conditions, karyotyping studies suggest that one X and one Y chromosomes are present in males, when an extra Y chromosome incorporates into the genome, it becomes XYY.

The structure of X and Y chromosomes.

XYY syndrome:

Other names: XYY syndrome, YY chromosome, Jacob’s syndrome, 47, XYY syndrome or supermale. Previously, it was believed that a person with the present conditions is overaggressive and lacking empathy although it was just rumored.

(nonsense science: people might though two YY cause overproduction of phenotypes related to it).

Technically, a person with an extra Y chromosome has learning and behavior problems (at some extend) but won’t have serious health conditions.

Jacobs published the first report of XYY syndrome in 1966. The XYY syndrome is a condition known as aneuploidy in which one extra Y chromosome is present with a pair of X and Y.

It occurs in males only with the frequency of 1 in 1,000 newborns worldwide. No severe physical symptoms are associated with the present condition.

It occurs during the meiosis cell division of sperm cells through the event called nondisjunction in which the Y chromosome gets duplicated. When it participates in the embryo formation it causes a male fetus with extra Y chromosomes- the XYY syndrome.

Note that the present conditions can’t be inherited, in addition, no clear reason for XYY to occur is to date reported. The symptoms and signs of the condition vary from person to person and age to age. Some common symptoms are:

  • Weak muscle tone- hypotonia
  • Dealy or underdeveloped motor skills and difficult speech.
  • Mild infertility in some cases.

Besides other scattered symptoms are autism, attention difficulties and learning disabilities. Scientific data suggest that a person with XYY syndrome can live like a normal person but they are a bit taller than others.

Scientists use FISH and karyotyping techniques to diagnose the present conditions in which the karyotping is employed commonly. It’s a cheaper and trusted option.

A blood sample or amniotic fluid/chorionic villi sample is extracted from a normal person or prenatal sample, respectively. Samples process to cell culture, harvesting and microscopy to investigate a karyotype. The expert prepares a karyogram and evaluates the final condition.

Speech therapy, occupational therapy and Educational therapy are some treatment options available for XYY syndrome.

Now coming to another important point of this section (i don’t know how to tell you about that but it’s important, trust me). Why the symptoms are so moderate?

The reason is the inactivation of Y. When one of the two Y chromosomes gets transcriptionally inactive, the whole gene expression profile of the Y chromosome somewhat remains normal (the presence of another Y isn’t so noticeable).

If another Y chromosome activates, it might create some serious problems, no related data are present. As I said, technically only a single copy from the set of the Y chromosome is required.

Now it is yet not reported that in XYY, both Y chromosomes are transcriptionally active or not.

Now coming to our main question are only YY chromosomes possible? What do you think? The answer is there in the X chromosome, let me explain.

Very crucial and important genes for physical, cognitive and mental development which take part in various biological pathways and activities are present on the X chromosome.

Henceforth, the X chromosome is present in both males and females, however, in females, only a single X chromosome is transcriptionally active.

So imagine, if an X chromosome is absent in males what will happen?

It is not possible at all! No scientific data, literature, case study or patient report to date available showing the case of only YY chromosomes in males.


SRY and STS are perhaps the best characterised genes resident on the Y chromosome in terms of their brain and behavioural functions, although it must be acknowledged that in many respects our knowledge about the role of these two genes is lacking. However, there are several other Y-linked genes in NRY, which, in that they are expressed in the brain, could also potentially contribute towards neural sexual differentiation. Xu and colleagues described six NRY genes (Dby (now Ddx3y) Ube1y, Smcy (now Kdm5d), Eif2s3y, Uty, and Usp9y) which were expressed at one or more developmental stages in male and 40,XY female mouse brain (the latter indicating a lack of requirement for testicular secretions)[98]. Of the genes analysed, all had an X-linked homologue, which was definitively known to escape X-inactivation in three cases (Smcx/Kdm5c, Utx and Eif2s3x). In several cases, the expression of the Y homologue in males was much lower than its X-linked homologue, and as such was not sufficient to ensure dosage compensation between the sexes. A further intriguing possibility when considering the genetic mechanisms underlying sexually dimorphic brain phenotypes, is that X and Y-linked homologues, in addition to being expressed at different levels, are expressed at different developmental stages and/or in different brain regions. Indeed, recent work by Xu et al. has shown that the paralogues Utx and Uty are differentially expressed in the paraventricular nucleus of the hypothalamus (high Uty expression) and in the amygdala (high Utx expression), possibly as a consequence of differential epigenetic marks [99]. To our knowledge, no comprehensive survey comparing the relative spatiotemporal expression dynamics of X and Y homologues has yet been performed, although it has been shown that that there is some consistency in the expression patterns of Eif2s3y and Eif2s3x, with highest expression of both in the thalamus, hypothalamus, hippocampus and cerebellum [100]. The expression patterns for many mouse NRY genes are now documented in resources such as the Allen Brain Atlas: of the Y-linked genes mentioned above, Ube1y and Eif2s3y are highly expressed throughout the hypothalamus. As the pituitary gland is pivotal in the secretion of hormones underlying sex-specific physiology, it would be worthwhile examining the expression of Y-linked genes in specific endocrine cell types of this tissue. In many cases, the brain and behavioural functions of NRY-linked genes are obscure, a fact probably attributable to the structural nature of the Y chromosome precluding the development of knockout models. Insights into the range of neural functions underpinned by NRY genes are likely to come from Y-chromosome mutant mice (in which Y-linked genes are spontaneously deleted or duplicated) alternatively, insights may come from a comparison of normal male mice and 39,X m O mice [65], the two groups only differing in the fact that the latter has no Y chromosome.

There are human orthologues of Ddx3y, Kdm5d, Uty and Usp9y, therefore investigations in mouse models into the neurobiological functions of these genes are likely to shed light upon their role in male brain development in humans. There appear to be species differences between mice and humans with regard to some Y-linked brain-expressed genes, in that Ube1y and Eif2s3y have no human counterparts, whilst ZFY appears to be expressed in the hypothalamus and cortex of adult humans [52], but is not expressed at any developmental stage in mouse brain [98]. Hence, it is likely that the nature of the neural sexual differentiation process is, to a greater or lesser extent, species-specific. One X-Y homologous gene pair which has received a lot of interest regarding its role in neurodevelopment is PCDH11X/Y. The homologous genes are located within a hominid-specific region of the sex chromosomes (Xq21.3 and Xp11.2), and encode members of the protocadherin superfamily responsible for cell-cell interactions during development of the central nervous system [101]. Not only are PCDH11X and its Y counterpart structurally different (and therefore possibly functionally distinct) but they have been shown to exhibit differential expression patterns, most likely because the two genes possess different promoter regions [101]. In the brain, transcripts from both PCDH11X and PCDH11Y are present most highly in the cortex [102], and also in several subregions including the amygdala, caudate nucleus, hippocampus and thalamus [101]. Interestingly, PCDH11X seems to be the preferential transcript in the cerebellum in the heart, transcripts are predominantly from PCDH11X, whereas in the kidney, liver, muscle and testis transcripts come mainly from PCDH11Y [101]. Together these data indicate that PCDH11X/Y genes may play key modulatory roles in the sexual differentiation of a wide variety of organs (including the brain) in hominid mammals. Exactly how PCDH11Y may act in the brain to modulate function remains to be resolved, but work in prostate cancer cell culture suggests that it may influence neuroendocrine tissue transdifferentiation via classical Wnt signalling pathways [103].

The X and Y of sex differences

Why and how are men and women different? My interest in this topic is fuelled by my research on neurodevelopmental disorders of language and literacy that typically are much more common in males than females. In this post, I am ranging far from my comfort zone in psychology to discuss what we know from a genetic perspective. My inspiration was a review in Trends in Genetics by Wijchers and Festenstein called “Epigenetic regulation of autosomal gene expression by sex chromosomes”. Despite the authors' sterling efforts to explain the topic clearly, I suspect their paper will be incomprehensible to those without a background in genetics, so I'll summarise the main points - with apologies to the authors if I over-simplify or mislead.

So, to start with, some basic facts about chromosomes in humans:
• We have 23 pairs of chromosomes, one member of each pair inherited from the father, and the other from the mother.
• For chromosome pairs 1-22, the autosomes, there is no difference between males and females.
• Chromosome pair 23 is radically different for males and females: females have two X chromosomes, whereas males have an X chromosome paired with a much smaller Y chromosome
• The Y chromosome carries a male-determining gene, SRY, which causes testes to develop. The testes produce male hormones which influence body development to produce a male.
• The X chromosome contains over 1000 genes, compared to 78 genes on the Y chromosome.
• In females, only one X chromosome is active. The other is inactivated early in development by a process called methylation. This leads to the DNA being formed into a tight package (heterochromatin), so genes from this chromosome do not get expressed. X-inactivation randomly affects one member of the X-chromosome pair early in embryonic development, and all cells formed by division of an original cell will have the same activation status. The patches of orange and black fur on a calico cat arise when a female has different versions of a gene for coat colour on the two X chromosomes, so patches of orange and black fur occur at random.
• In both X and Y chromosomes, there is a region at the tip of the chromosome called the pseudoautosomal region, which behaves like an autosome, i.e., it contains homologous genes on X and Y chromosomes, which are not inactivated, and which recombine during the formation of sperm and eggs.
• In addition, a proportion of genes on the X chromosome (estimated around 20%) escape X-inactivation, despite being outside the pseudoautosomal region.

These basic facts are summarised in Figure 1. Genes are symbolised by red dots, grey shading denotes an inactivated region, and yellow is the pseudoautosomal region.

Figure 1
Note that because (a) the male Y chromosome has few genes on it and (b) one X chromosome is largely inactivated in females, normal males (XY) and females (XX) are quite similar in terms of sex chromosome function: i.e., most of the genes that are expressed will come from a single active X chromosome.
Studies of mice and other species have, however, demonstrated differences in gene expression between males and females, and these affect tissues other than the sex organs, including the brain. Most of these sex differences are small, and it is usually assumed that they are the result of hormonal influences. Thus the causal chain would be that SRY causes the testes to develop, the testes generate male hormones, and those hormones affect how genes are expressed throughout the body.

You can do all kinds of things to mice that you wouldn't want to do to humans. For a start you can castrate them. You can then dissociate the effect of the XY genotype from the effect of circulating hormones. When this is done, many of the sex differences in gene expression disappear, confirming the importance of hormones.
There's some evidence, though, that this isn't the whole story. For a start, it is possible to find genes that are differently expressed in males and females very early in development, before the sex organs are formed. These differences can't be due to circulating hormones. You can go further and create genetically modified mice in which chromosome status and biological sex are dissociated. For instance, if Sry (the mouse version of SRY) is deleted from the Y chromosome, you end up with a biologically female mouse with XY chromosome constitution. Or an autosomal Sry transgene can be added to a female to give a male mouse with XX constitution. A recent study using this approach showed that there are hundreds of mouse genes that are differently expressed in normal XX females vs. XY females, or in normal XY males vs. XX males. For these genes, there seems to be a direct effect of the X or Y chromosome on gene expression, which isn't due to hormonal differences in males and females.

Wijchers and Festenstein consider four possible mechanisms for such effects.
1. SRY has long been known to be important for development of testes, but that does not rule out a direct role of this gene in influencing development of other organs. An in mice there is indeed some evidence for a direct effect of Sry on neuronal development.
2. Imprinting of genes on the X chromosome. This is where it starts to get really complicated. We have already noted how genes on the X chromosome can be inactivated. I've told you that X-inactivation occurs at random, as illustrated by the calico cat. However, there's a mechanism known as imprinting whereby expression of a gene depends on whether the gene is inherited from the father or the mother. Imprinting was originally described for genes on the autosomes, but there's considerable interest in the idea of imprinting affecting genes on the X chromosome, as this could lead to sex differences. The easiest way to explain this is by a mouse experiment. It's possible to make a genetically modified mouse with a single X chromosome. The interest is then in whether the single X chromosome comes from the mother or the father. And indeed, there's growing evidence for differences in brain development and cognitive function between genetically modified mice with a single maternal or paternal X chromosome: i.e., evidence of imprinting. Now this has implications for sex differences in normal, unmodified mice. XY male mice have just one X chromosome, which always comes from the mother, and will always be expressed. But XX female mice have a mixture of active maternal and paternal X-chromosomes. Any effect that is specific to a paternally-derived X-chromosome will therefore only be seen in females.
What about humans? Here we can study girls with Turner syndrome, a condition in which there is one rather than two X chromosomes. Skuse and colleagues found differences in cognition, especially social functioning between girls with a single maternal X vs. those with a single paternal X. There are few studies of this kind, because it is difficult to recruit large enough samples, so the results need replicating. But potentially this finding has tremendous implications, not just for finding out about Turner syndrome itself, but for understanding sex differences in development and disorders of social cognition.
3. Although most X-chromosome genes are expressed from only one X-chromosome, as noted above, some genes escape inactivation, and for these genes females have two active copies. In the main, these are genes with a homologue on the Y-chromosome, but there are exceptions, and in such cases females have twice the dosage of gene product compared to males (see Figure 1). And even where there is a homologue gene on the Y chromosome, this may have different effects from the active X-chromosome gene.
4. The Y chromosome contains a lot of inactive DNA with no genes. Recent studies on fruit flies has found that this inactive DNA can affect expression of genes on the autosomes, by affecting availability in the cell nucleus of factors that are important for gene expression or repression. It's not clear if this applies to humans.

My interest in this topic has led me to study children who do not inherit the normal complement of sex chromosomes. These include girls with a single X chromosome (XO, Turner syndrome), girls with three X chromosomes (triple X or XXX syndrome), (see figure 2) and boys with an extra X (XXY or Klinefelter’s syndrome), and boys with an extra Y (XYY syndrome).(see Figure 3).

Figure 2

Figure 3
Affected children typically don’t have intellectual disability and attend regular mainstream school. As illustrated in Figures 2 and 3 , this makes sense because the genetic differences between those with missing or extra sex chromosomes and those with the normal XX or XY complement are not great. In Turner syndrome there is only one X chromosome, whereas children with XXX or XXY will have all but one X chromosome inactivated. The extra Y in boys with XYY contains only a few genes.

Nevertheless, although children with atypical sex chromosomes are not severely handicapped, distinctive neuropsychological profiles have been described. Girls with Turner syndrome often have poor visuospatial function and arithmetical ability, whereas language skills are typically impaired in children with an extra sex chromosome. To explain these effects, researchers have proposed a role for genes that normally escape inactivation, which will be underexpressed in Turner syndrome, or over-expressed in children with three sex chromosomes (sex chromosome trisomy) - see point 3 above.

Wijchers and Festenstein note the importance of individuals with sex chromosome anomalies for informing our understanding of sex chromosome effects on development, but their account is not very satisfactory, as they state that “females with triple X syndrome (47,XXX) seem normal in most cases.” Although it is the case that many girls with XXX go undetected, surveys of prenatally or neonatally identified cases indicate that they have cognitive problems. Language deficits are found at high levels in all three cases of trisomy, XXX, XXY and XYY, with a trend for lower overall IQ in girls with XXX than boys with XXY or XYY. We did a study based on parental report, and found a diagnosis of autism spectrum disorder was more common in boys with XXY and XYY than in boys with normal XY chromosome status. But there was considerable variability from child to child, with some having no evidence of any educational or social difficulties, and others with more serious learning difficulties or autism. We currently lack data that would allow us to relate the cognitive profile in such children to their detailed genetic makeup, but this in an area researchers are starting to explore. We are optimistic that such research will not only be helpful in predicting which children are likely to need additional help, but also may throw light on more global questions about the genetic basis of sex differences in cognitive abilities and disabilities.

What are the implications of this research for the debate about sex differences in everyday human behaviour? This was very much in the news in 2010 with the publication of Cordelia Fine’s book Delusions of Gender, which was reviewed in The Psychologist, with a reply by Simon Baron-Cohen. Fine focused on two key issues: first, she questioned the standards of evidence used by those claiming biologically-based sex differences in behaviour, and second she noted how there were powerful cultural factors that affected gender-specific behaviour and that were all too often disregarded by those promoting what she termed ‘neurosexism’. I don’t know the literature well enough to evaluate the first point, but on the second, I would agree with Fine that biological factors do not occur in a vacuum. The evidence I’ve reviewed on genes shows unequivocally that there are sex differences in gene expression, but it does not exclude a role for experience and culture. This is nicely illustrated by the research of Michael Meaney and his colleagues demonstrating that gene expression in rats and mice can be influenced by maternal licking of their offspring, and that this in turn may differ for male and female pups! Genes are complex and fascinating in their effects, but they are not destiny.

Further reading
Davies, W., & Wilkinson, L. S. (2006). It is not all hormones: Alternative explanations for sexual differentiation of the brain. Brain Research, 1126, 36-45. doi: 10.1016/j.brainres.2006.09.105.
Gould, L. (1996). Cats are not peas: a calico history of genetics: Copernicus.
Lemos, B., Branco, A. T., & Hartl, D. L. (2010). Epigenetic effects of polymorphic Y chromosomes modulate chromatin components, immune response, and sexual conflict. Proceedings of the National Academy of Sciences, 107(36), 15826-15831.doi/10.1073/pnas.1010383107.
Skaletsky, H., Kuroda-Kawaguchi, T., Minx, P. J., Cordum, H. S., Hillier, L., Brown, L. G., et al. (2003). The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature, 423(6942), 825-837.doi: 10.1038/nature01722

Wijchers PJ, & Festenstein RJ (2011). Epigenetic regulation of autosomal gene expression by sex chromosomes. Trends in genetics : TIG, 27 (4), 132-40 PMID: 21334089