Scientists generate XX and XY cells from a person with Klinefelter syndrome
scientificamerican.com
scientificamerican.com
> "Although some of the sex differences arise from hormonal effects (Gurvich et al., 2018), it is now acknowledged that many differences are due to sex chromosome complement (Arnold, 2012). Studying the effects of sex chromosome complement on gene expression and biological phenotypes is impeded by variation in genetic background. Therefore a large sample size is needed to identify sex-related differences (Ronen and Benvenisty, 2014). To date, there is no human model to study sex differences that can overcome the variation in genetic background."
Another complicating factor must be the random nature of X-chromosome inactivation in XX cells, as only one of the two copies is actively transcribed. Hence even if you clone an XX-type cell, its progeny cells will at some point randomly (and permanently) switch off one of those X chromosomes (to avoid making too many gene products).
> "The two X chromosomes have an equal probability of being silenced. Silencing, once established, is stable: the same X chromosome remains inactivated in all subsequent cell generations. As a result, each female is a mosaic of cells in which either the maternally inherited or the paternally inherited X is silenced."
For those curious about it, a visual example of this is tortoiseshell and calico cats.
The orange or black in a cat is X linked. A simple, not quite correct, representation of this would be that a male cat can be either XoY or XbY while a female cat can be XoXo, XoXb, XbXb. The XoXb cats are both black and orange and are frozen at the time when one of the chromosomes were silenced.
This is known as X-inactivation and the Wikipedia page ( https://en.wikipedia.org/wiki/X-inactivation ) even has a picture of a tortoiseshell cat.
When this goes wrong, genetic disease can occur such as what happens with Angel man and Prader willi syndrome, which is caused by the exact same mutation but dependent on the sex of the parent it was inherited from.
So, the title is rather misleading. They just had to get cells to shed one of the three chromosomes, they didn't get an XX female to somehow produce a Y, nor an XY male to duplicate their X.
None of us will have heard of Klinefelter syndrome before, but maybe that's a good thing.
Edit: for those downvoting, can you tell me how I’m wrong, if that is the case?
>Please don't comment about the voting on comments. It never does any good, and it makes boring reading.
The replies since then have been interesting and not boring at all. Until I got to yours.
Instead, they're probably talking about taking three cells with XY, and then using that to create an xx, an xy, and then some leftover parts.
If that is the case, your correction might seem arrogant or assuming.
So it seems like making XX from a single XY person would just end up doing something genetically similar to what already happens with marsupials, which doesn't result in non-viability.
Of course, cloning at all does result in not getting genetic diversity you would normally get from recombination, which can eventually result in population-level problems if you're doing enough of it.
While in males there is no recombination between the X and Y chromosomes, in females sometimes there is recombination between the two X chromosomes.
Therefore the X chromosome received by a child from the mother may either be 1 of the 2 X chromosomes of the mother, chosen randomly, or it may be a combination of those 2 X chromosomes.
The inactivation of an X chromosome happens only in the female somatic cells, where the remaining active X chromosome is either the X chromosome of the father or 1 of the 2 X chromosomes of the mother or a combination of the 2 X chromosomes of the mother.
SRY can cross over to the X chromosome (resulting in an XX male), but the end result is usually sterile as there are other genes elsewhere on the Y chromosome that are also necessary for complete development.
What's more, with X inactivation, one of the chromosomes in XX becomes almost completely inactive and all of the genes on the other chromosome are expressed.
https://en.wikipedia.org/wiki/X-inactivation
> X-inactivation (also called Lyonization, after English geneticist Mary Lyon) is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a transcriptionally inactive structure called heterochromatin. As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome (see dosage compensation).
There is a huge distance between "almost completely inactive" and "inactive". A Turner's syndrome patient (only one X chromosome) usually has several obvious physical defects, including sterility.
Interestingly, as far as I'm aware the things we usually think of as "X-linked" (more common in men, inherited as a recessive phenotype on the X chromosome - things like red/green colorblindness and male-pattern baldness) aren't as common in Turner's patients as you might expect.
Sure. Your claim that X is not female is correct. Your claim that Y is not male is wrong. Y is male. If one or more Y chromosomes are present, a male will develop, and if zero or fewer are present, a female will develop.[1]
Cloning a normal male's single X chromosome would lead to the type of problems familiar from inbreeding, but would be unlikely to lead to nonviability; two different X chromosomes, which all normal women have, are already too many and parts of them must be inactivated so that normal development can proceed.
The Y chromosome is unimportant enough that chromosomal abnormalities generally leave the organism in a viable, if often defective, state. The subject of this experiment is an example, with three (XXY) sex chromosomes. One X chromosome and no Y chromosomes (which would usually be described "XO", not "X") would get you a female with Turner syndrome.
In a handy table:
X alone: female, Turner syndrome
Y alone: male, but nonviable; this will be a miscarriage.
XX: female, normal
XY: male, normal
YY: male, nonviable
XXX: female, triple X syndrome
XXY: male, Klinefelter syndrome
XYY: male, Jacobs syndrome
YYY: male, nonviable
[1] There is an exception related to androgen insensitivity. There you have a genetic male that develops into what is mostly a phenotypic female. Such people have female psychology and female external anatomy, but they do not have a female reproductive system and are therefore sterile.
Everything about primary and secondary sex characteristics would not be affected by changing someone's chromosomes. Homologous sex structures diverge before birth based primarily on dht metabolism. Even then, chromosome expression doesn't always determine how dht will metabolize, meaning whatever chromosomes a person has can still lead to someone having any kind of primary and secondary sex characteristics. The six most common sex chromosome patterns in humans are XX, XY, XXY, XYY, X, and XXXY (in that order).
Sex and gender are both far more complex than merely chromosome expression, and chromosome expression is anything but a binary. This study has nothing to do with being male or female.
> “This is a very well-designed study that validates the notion that sex differences start early in development—and that they depend on the sex chromosomes because that’s the only thing that can account for those differences,” says Nora Engel, a professor of cancer and cell biology at Temple University, who was not involved in this work.
Is this your area of expertise?
There's two problems here. One is that XX/XY is not even a majority of the common human chromosome karyotypes, and changing karyotypes does not change someone's sex characteristics; those are determined at one specific moment during gestation, which may or may not be affected by changing the chromosomes beforehand, but certainly would not be affected by changing their chromosomes after that moment. Primary and secondary sex characteristics are determined by androgen metabolism, not by chromosome karyotypes.
Secondly most of the human karyotypes are not assigned a sex until some time after birth, and XY is often assigned female at birth because the divergence of homologous structures depends on androgen metabolism, not chromosome karyotype. Sex and gender don't exist for cell lines in the same way they do for people.
TL/DR; This is an article about a study that found they could change a cell line's karyotype, not a person's sex characteristics which are determined not by chromosome karyotypes but by androgen metabolism during gestation. Whoever wrote the headline didn't understand the topic.
There is far more to human biological sex than the chromosomal distinction. Take an XY cell, but it in an otherwise female body, and it will, in many ways, express itself similar to that of an XX cell. This is the theory behind hormome replacement therapy (HRT).
That is not to say that an XY cell in a female body would be identical to an XX cell in the same. For instance, an XY eye in a female body would likely be similar to a male eye with regards to color blindness; because we have traced colorblindness directly to a chromosonal difference.
However, most sex differences (in humans) are not chromosonal. Instead they are triggered by a single gene (SRY), that just so happens to occur on the Y chromosone. That single gene codes for a protein that triggers almost all of the sex differentiation. Splice that single gene onto a X chromosome and you can get an XX human that appears male.
Exactly what differences are directly chromosomal, and what are developmental is a largly open area of research, and exactly what this achievement hopes to further enable.
We can go on about male v female as a social construct, but biologically, males produce the smaller gamete, so if one has SRY and has an otherwise male phenotype, but isn't producing sperm, from a strictly biological perspective, it's not at all clear that the statement 'SRY is the determinant of maleness' is necessarily true.
It certainly will make you develop testicles and male secondary sex characteristics.
You are correct on the cell naming. Cells cannot be male or female. That is a characteristic of a complete person. They can be derived from a male or female, but what the scientists did here did not change that attribute of a cell.
Note that we replaced it with what the article itself says it's about, once it gets to the stage of actually saying that.
You can put a woman's X chromosome in a sperm but it'll be labelled "from mum" and not work quite right.
See Prader Willi and Angleman syndrome for examples.
Since men (typically) only have one X chromosome to start, the X passed in their sperm is identical to that of their somatic cells. So two sisters with the same parents will share one identical X from their father, but the second X from their mother will be different combinations of her two X's.
Edit to add: if genetic recombination didn't happen, then lots of siblings would end up as genetic twins. (50% chance within the same gender). And that would also be identical to the offspring from one crossing one grandparent on each side... Fortunately this doesn't happen!
That's not the same as creating male embryos deliberately.
> A laminar-flow fractionation method, developed primarily for removing dead sperm from human semen, was successfully modified to enrich X and Y sperm to 80% purity, and to characterize each enriched fraction for individual swimming behavior. Y-sperm fractions were rapidly detected by fluorescent cytogenetic staining. Subsequently, the degree of enrichment was quantitated with DNA extracted from each sperm fraction probed with a human male-specific recombinant DNA clone. In stationary fluid, X and Y sperm swam in circles with the same average speed. However, in a flowstream, X sperm shifted to a nearly straight path of movement in a significantly decreased angular velocity. This shift was four times more pronounced in X sperm than in Y sperm, especially after the initial transition from stationary fluid to flow. The velocity gradient across the flow axis was essential for separating X and Y sperm; uniform flow velocity did not separate them effectively.
AMA Journal of Ethics - Sex Selection for Family Balancing https://journalofethics.ama-assn.org/article/sex-selection-f...
> Currently, there are three available methods for sex selection. The first option is prefertilization sperm sorting using flow cytometry, which can provide a semen sample enriched with sperm that bear the desired sex chromosome. Its accuracy is in the 84-92 percent range, and it is not yet available in the US [6, 7]. At the opposite end of the spectrum, the most extreme form of sex selection occurs after conception in the form of elective termination of pregnancy if prenatal testing shows the sex of the fetus is the opposite of that desired. In certain regions of the world, such as India, such procedures are commonly performed, despite being illegal [8, 9].
This is also why "cloning dinosaurs" might be extremely difficult even if you found complete DNA, you lack compatible enough hardware to run that DNA on.
It's the old bootstrapping problem - how do you get a running C compiler from code if you don't already have a running C compiler?
There is no example in nature where you get a fully functional cell starting exclusively from DNA.
As in most absolute statements, this may not be completely true. Sperm has some mitochondria that likely is incorporated into the zygote.[1]
[1] https://en.wikipedia.org/wiki/Paternal_mtDNA_transmission
The controversy about human paternal leakage was summed up in the 1996 study Misconceptions about mitochondria and mammalian fertilization: Implications for theories on human evolution, which was peer-reviewed and printed in Proceedings of the National Academy of Sciences.[15] According to the study's abstract:
In vertebrates, inheritance of mitochondria is thought to be predominantly maternal, and mitochondrial DNA analysis has become a standard taxonomic tool. In accordance with the prevailing view of strict maternal inheritance, many sources assert that during fertilization, the sperm tail, with its mitochondria, gets excluded from the embryo. This is incorrect. In the majority of mammals—including humans—the midpiece mitochondria can be identified in the embryo even though their ultimate fate is unknown. The "missing mitochondria" story seems to have survived—and proliferated—unchallenged in a time of contention between hypotheses of human origins, because it supports the "African Eve" model of recent radiation of Homo sapiens out of Africa.