Course: Biology library > Unit 16Lesson 4: Sex linkage, chromosomal mutations, & non-nuclear inheritance
How XX human females (and other female mammals) shut down one of their X chromosomes in each cell. Disorders of sex chromosome number: Klinefelter, triple X, and Turner syndromes.
Having extra or missing chromosomes is not usually a good thing. In fact, for most chromosomes, having an extra or missing copy is lethal to humans (causing an embryo to die early in development).
Yet, human females have two X chromosomes (XX), while human males have just one (XY). Why doesn't it cause problems for men to have just one copy of the X chromosome, while women have two?
As it turns out, the level of gene activity produced by a single X chromosome is the normal "dosage" for a human. Men have this dosage because, well, they only have one X chromosome! Women have the same dosage for a different reason: they shut down one of their two X chromosomes in a process called X-inactivation.
In X-inactivation, an X chromosome is compacted (or, as my intro bio professor liked to say, "crumpled up into a ball"), to make a small, dense structure called a Barr body. Most of the genes on the Barr body are inactive, meaning that they are not transcribed. The process of X-inactivation was discovered by the British geneticist Mary F. Lyon and is sometimes called lyonization in her honor.
Photograph of Mary F. Lyon, discoverer of X-inactivation.
A woman has two X chromosomes, one from each parent. Which one will she inactivate? X-inactivation is a random process that happens separately in individual cells during embryonic development. One cell might shut down the paternal X, while its next-door neighbor might shut down the maternal X instead. All the cells descended from each of these original cells will maintain the same pattern of X-inactivation.
Interesting note: if you were a kangaroo, what I just said would not be true! In kangaroos and other marsupials, it is always the paternal X chromosome that undergoes X-inactivation.
X-inactivation example: Calico cat
A classic example of X-inactivation is seen in cats. If a female cat is heterozygous for black and tan alleles of a coat color gene found on the X, she will inactivate her two Xs (and thus, the two alleles of the coat color gene) at random in different cells during development.
The result of is a tortoiseshell coat pattern, made up of alternating patches of black and tan fur. The black patches come from groups of cells in which the X with the black allele is active, while the tan patches come from cells in which the X with the tan allele is active.
Image of a tortoiseshell cat, illustrating the X-inactivation processes responsible for the different patches of color on its coat. The cat has a mix of black and tan patches of fur, some small and some large. The cat's genotype is , where the large O stands for orange and the small o stands for black.
- The orange patch is made up of cells in which the X with the orange allele () is active, while the X with the black allele () is compacted into a Barr body.
- The black patch is made up of cells in which the X with the black allele () is active, while the X with the orange allele () is compacted into a Barr body.
Although it's rarely as easy to see as in the case of the tortoiseshell cat, human females are also "mosaic" for any genes that are present in different alleles on their two X chromosomes.
Sex chromosome aneuploidies
When an organism has an extra or missing copy of a chromosome, it is said to be aneuploid. Aneuploidies involving autosomes (non-sex chromosomes), especially large ones, are usually so harmful to development that an aneuploid embryo can't survive to birth.
Aneuploidies of X chromosomes, however, tend to be much less harmful, despite the fact that the X is a large chromosome. This is mostly thanks to X inactivation. Although the purpose of the X-inactivation system is to shut down the second X of an XX female, it can also do a pretty good job of shutting down more X chromosomes if they are present.
Examples of X chromosome aneuploidies include:
- Triple X syndrome, in which a woman has an XXX genotype, which occurs in about out of every female newborns. Women with an XXX genotype have female sex characteristics and are fertile (able to have children). In some cases, triple X syndrome may be associated with learning difficulties, late development of motor skills in infants, and problems with muscle tone.
- Klinefelter syndrome, in which males have an extra X chromosome, leading to a genotype of XXY. (In rarer cases, Klinefelter syndrome can involve several extra Xs, leading to an XXXY or XXXXY genotype.) Affected men may be infertile or develop less dense body and facial hair than other men. Klinefelter syndrome is thought to affect out of every to male newborns.
Like females, XXY males with Klinefelter syndrome will convert one X to a Barr body in each cell. Triple X females (as well as Klinefelter males with more than two X chromosomes) neutralize their extra Xs by forming additional Barr bodies. For example, there would be two Barr bodies in a cell from an XXX female or XXXY male.
Diagram showing sex chromosomes and Barr body formation in human individuals with different sex chromosome genotypes.
XX female: one active X, one Barr body. XY male: one active X, one Y, no Barr body. XXY male (Klinefelter syndrome): one active X, one Y, one Barr body. XXX female (triple X syndrome): one active X, two Barr bodies.
in Turner syndrome, a woman lacks part or all of one of her X chromosomes (leaving her with just one functional X). People with this disorder develop as females, but often have short stature and may exhibit symptoms like infertility and learning difficulties. Turner syndrome is thought to occur in about out of every female births. It has relatively mild effects because humans normally have only one X active in the cells of their body anyway.
Check your understanding
Although most tortoiseshell cats are female, a litter of kittens will occasionally contain a male tortoiseshell. Which of the following can explain tortoiseshell coat color in a male kitten?
Want to join the conversation?
- If the extra copy of X chromosome is inactivated by Barr bodies, why does XXX or XXY show an abnormal phenotype? Is the inactivation not perfect (i.e leaky)?(21 votes)
- Excellent question. X inactivation happens in XXY males, as well as normal XX females. However, in XXY males, a few genes located in the pseudoautosomal regions of their X chromosomes have corresponding genes on their Y chromosome and are capable of being expressed. This means even though the extra X is deactivated, during recombination in Meiosis 1 there may be exchange of genes between X and Y and would result in expression of these traits.(16 votes)
- And about that, how will the inactivated X chromosome be when it undergoes meiosis to produce gametes?(17 votes)
- @Junsang is right, the compact X chromosome winds open during meiosis undergoes gamete production normally.(4 votes)
- Given the explanations above, how does Swyer syndrome occur? (a person who is typically raised as female and has female external genitalia but also has a Y chromosome) I noticed this in the 2016 Olympics, as it was hotly debated with track and field.(12 votes)
- hmm.. perhaps the Y chromosome is missing an SRY gene? would love to hear from an expert(4 votes)
- In Turner's syndrome, the individual has 45 chromosomes of the karyotype XO (only one X chromosome), and displays mental retardation and physical abnormalities, among other symptoms,while a zygote with two X chromosomes would develop as a normal female.Why is that? Wouldn't one of the X chromosomes be inactivated anyway?(6 votes)
- Great question!
At least one factor that contributes to this is that the X (and Y) chromosomes have what are called pseudoautosomal regions (PARs).
The PARs allow crossing over between the X and Y — this allows for meiotic pairing, crossing over, and disjunction of the X and Y in males.
The PARs are not X-inactivated and so are thought to contribute to the defects associated with sex-chromosome aneuploidy including Turner's syndrome.
For example Turner's syndrome patients are usually short and one PAR gene, SHOX, is a transcription factor that promotes skeletal development particularly bone growth in the arms and legs.(7 votes)
- Can a malfunction happen in which both X chromosomes stay active somehow, and would that be lethal? Could that ever happen?(6 votes)
- Good question. From what I've found so far:
The mechanism of inactivation is still not very well understood, but there are some theories.
In mice, there are 2 events of inactivation. It is known that inactivation happens in females and also in males and cases which have an extra X chromosome.
In the fisrt, the event of inactivation fraternal X (Xp) is inactivated, and in the late blastocyst, second inactivation event happens. This time fraternal Xp reactivates and now random inactivation happens.
Meaning that it never catches both X chromosomes.
I guess mutations can happen. However, it is hardly possible that in every single cell of the female body both X chromosomes are inactivated. If that happens I suppose it would be lethal and cause severe bodily malfunctions.
If both X chromosomes are inactivated in some cells, that female is a chimera.
Also, bear that: X chromosome inactivation is not an all-or-none phenomenon. Of the 2000 or so X-linked genes on the X chromosome, about 10% are not inactivated by X inactivation of the chromosome on which they lie. Thus, these genes maintain two actives, transcribed and translated copies in individuals with two X chromosomes.
May this photo help:
- It's stated that the extra X chromosome in people with Klinefelter syndrome will be inactivated. Since it's been inactivated, by right, it'd virtually be the same as normal people, isn't it? But why is it people with Klinefelter syndrome still have abnormalities? Thank you.(4 votes)
- As stated by Dr. Barry Starr, "the problem comes from the fact that X inactivation is not complete. X inactivation starts at the middle of the chromosome and spreads towards the ends. Apparently it peters out before it makes it all the way. The genes at the ends that are still on lead to Klinefelter's syndrome. In fact, many of the symptoms of Klinefelter's are really those of a feminized male." Link to the full article: http://genetics.thetech.org/ask/ask141(4 votes)
- But my question is that some X. Linked dominant disorder like alpart syndrome etc if the defective allele come in heterozygous can cause problems what's about the other normal allele (recessive)??(4 votes)
- Well, normal allele cannot do much in that case since it is recessive.
What you ask is, what if X on which dominant allele is, gets inactivated? In that case, it is not heterozygous and the normal allele is only expressed.
But, there is a tricky part. What if during crossing over, dominant allele got onto X which will stay active? In that case, the syndrome will manifest.(3 votes)
- (Under Sex chromosome aneuploidies topic)
What about Just Y chromosome in male (relative to the non dis-junction of sex chromosome)? Will it result in fetal death as there's no X chromosome at all?(4 votes)
- only Y will be spontaneous abortion, at least one X required to be viable. because X has more expressed genes than Y.(3 votes)
- In turners syndrome there is absence of one x chromosome.but another x chromosome ia still present.then why doesn't this x chromosome perform its normal functions?.afterall both the x chromosomes have similar genes,and there is no barr body in turners syndrome.(5 votes)
- That is correct. There is no Barr body in Turners because they only have one X. So instead of being XX female or XY male, Turner individuals are just X (typically denoted “XO” to show the absence of the second sex chromosome).
This X does exactly what you mentioned! The genes are expressed from this one-and-only X. It is the organism’s only hope!(0 votes)
- During x inactivation, is it either paternal or maternal X that are silenced or both ?(2 votes)
- In humans and mice, it is a random choice. At first, it is only paternal, but during the second inactivation event, fraternal reactivates and then random one inactivates.(2 votes)