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X Chromosomes in a New Light

x chromosome silencing

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#1 xEva

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Posted 22 January 2014 - 08:14 PM


An interesting article in NYT Seeing X Chromosomes in a New Light

It says that females silence one of the 2 inherited X chromosomes at random. But I'm a bit confused --does this silencing apply only to X chromosomes? What about other pairs? I thought that all chromosomes come in pairs, one from each parent, and yes, males get one odd XY pair, both of them supposedly active.

Can someone please tell me if similar silencing of one of the chromosomes in a pair also applies to other 22 pairs? Thanks :)

..and the other question, if one of the X chromosomes is silenced in females, while males have both X and Y active, this would imply that males have more active genes per cell, no?

#2 Darryl

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Posted 22 January 2014 - 09:35 PM

The X chromosome codes for 815 confirmed proteins.

The Y chromosome codes for 45 confirmed proteins.

By this measure, males have 0.23% more confirmed proteins in their genome than females (19313 vs. 19268).

Only the X-chromosome is silenced in this sort of global fashion - it prevents overexpression of constituitive genes from X in women. It probably also helps weed out deletorious mutations in germline cells that would be more harmful than mutations on other chromosomes.

A good visual representation of X-chromosome silencing is Calico cats.

Edited by Darryl, 22 January 2014 - 09:42 PM.

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#3 xEva

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Posted 22 January 2014 - 10:05 PM

Thank you Darryl!

So, no chromosomes in other pairs are silenced!

In the article it was also mentioned that a failure to silence one of the X chromosomes in females may increase incidence of cancer -? All this makes me wonder what's so special in X chromosome that distinguishes it from chromosomes in other pairs. What requires that only one X copy should be active per cell, while it's perfectly alright for both copies in all other pairs to be active.

Any ideas?

#4 Darryl

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Posted 22 January 2014 - 11:02 PM

The expression level of each gene is regulated by non-coding DNA sequences (promoters, enhancers, silencers) upstream of the the DNA that codes for the protein product. The affinity of the RNA polymerase complex and numerous tissue and cell-state specific transcription factors for these sequences determines (to a large extent) how often a given gene is transcribed and hence the concentration of its protein product in the cell. Promoters and the other non-coding regulatory sequences can either be strong, if they code for the consensus sequences recognized by the transcription factors and are near the coding DNA; or progressively more weak, if their sequence differs or they are more distant. As you might imagine, this allows for almost infinite fine-tuning of gene expression by evolution.

For genes on chromosomes other than X and Y, there are always two copies, though one or even both can encode mutant (usually ineffective) protein products. The tuning of these genes' expression can be adjusted in evolutionary time by natural selection on the regulatory sequences to achieve the right product levels. For genes on the Y chromosome, there is one copy (almost always: 1 in 1000 males is XYY, but most will never know it), and there too, the right product amounts can be dialed in. But every gene allelle on the X chromosomes can either exist either alone in males (about 1/3 of the time), or in the company of its complement in females (about 2/3 of the time), and there's no opportunity for the regulatory sequences to evolve between these states in successive generations. As the X chromosome, unlike Y, encodes many housekeeping genes vital to development and metabolism in both males and females, this situation could bring a bit of biological chaos. To prevent the copies of this gene from expressing twice as much product when in females than when in males, the simplest solution discovered by evolution is to simply silence one entire X chromosome.

Edited by Darryl, 22 January 2014 - 11:16 PM.

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#5 xEva

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Posted 23 January 2014 - 03:37 AM

Oh wow that's very interesting. Thanks again!

It sounds plausible but not terribly convincing though. The difference in rate of evolution of regulatory sequences could be compared to interbreeding among closely related species: and the latest evidence suggests that hominids did just that all the time, without apparent ill effects on their evolutionary course. This sort of thing can also happen when the age difference in breeding pairs is consistently large and skewed in a particular direction (which is a common thing in humans).

Also, if XYY males can handle their extra Y chromosome just fine, why can't females handle the second X? And the wiki article on calico cats says that male XXY cats can't quite handle that extra X chromosome either, cause it makes them infertile.

Also, what prevents the regulatory sequences to keep evolving mostly in females and just bestowing the ready gift on males?

Is it possible that there maybe something else to it?

The other thing I did not quite get was the 1/3 - 2/3 distribution for XY and XX pairs. I thought that gender distribution was close to 50-50 with the number of boys born being slightly greater than girls -? The difference cannot possibly account for triple sex chromosomes mutations, so what is it due?

Thank you :)



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Edited by xEva, 23 January 2014 - 03:48 AM.


#6 Darryl

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Posted 23 January 2014 - 07:56 AM

XYY carrier males don't quite handle their extra Y just fine: they have a higher incidence of learning difficulties, and perhaps as a consequence, are more likely to have criminal convictions. They also tend to be taller.

Back in the day, when our reptilian ancestors determined their sex by ambient temperature, the X chromosome was like the others, containing a fairly random selection of the genes required for development and metabolism. As you might imagine, ambient temperature wouldn't work well for sex determination in warm blooded placental mammals, so the mammalian system of sex determination by chromosomal bingo somehow started.

As Y diverged from X, it progressively lost most of the housekeeping genes made redundant by their continued presence on X. If the selection of genes noted on the Y chromosome Wiki page is representative, Y has lost all genes except a sparse number critical to sex determination, testis development, and spermatogenesis. Most of the genes for even these functions remain on other chromosomes, including X..


An extra copy of Y, which no longer codes for much, just leads to taller, marginally less bright guys. A 50% increase in the ~225 genes extra copy of chromosome 21, the smallest non-sex chromosome (coding for ~225 genes), results in Down syndrome. Without silencing, 100% increases in the ~815 genes in the X chromosome in females, or alternatively (and more appropriately, as female is the default gender), 50% reductions in males, would lead to some pretty vast gender differences.

With respect to that 1/3, 2/3 distribution, consider that among 100 people, 50 male and 50 female, there will be 150 X chromosomes. A X chromosome chosen at random from those 150 has a 1/3 chance of being from one of the males, and a 2/3 chance of being from one of the females. Likewise, every gene found on the X chromosome has spent 2/3s of its germline history in females, and 1/3 of its history in males.
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#7 xEva

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Posted 24 January 2014 - 02:46 AM

Thank you Darryl. Those are very interesting facts. Sounds like genetics is your field of expertise, is it?


I'm still having difficulty with this 1/3 - 2/3 distribution:

With respect to that 1/3, 2/3 distribution, consider that among 100 people, 50 male and 50 female, there will be 150 X chromosomes. A X chromosome chosen at random from those 150 has a 1/3 chance of being from one of the males, and a 2/3 chance of being from one of the females. Likewise, every gene found on the X chromosome has spent 2/3s of its germline history in females, and 1/3 of its history in males.


Only because in every generation an X gene has a 2/3 chance of being from one of the females and 1/3 chance from males, does not follow that its germline history was similarly distributed. History relates to time. And whenever 2 Xs are paired, their times run in parallel instead of being added consecutively. And so a 50-50 gender distribution results in 50-50 chance for any X to spend its time history with either Y or another X.

In other words, going from a static gender distribution in a given generation --> to the distribution of time spent in a gender, we would have to divide that 100 pool by 2, which gives us back 50-50.


I find genetics fascinating, but have not studied it systematically. Can you recommend an online resource? Thanks :)

Edited by xEva, 24 January 2014 - 02:47 AM.


#8 Darryl

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Posted 24 January 2014 - 04:19 PM

Alas, I missed the edit deadline before revising that to insert "generation" rather than "germline history".

• Gene copies residing on X chromosomes in women are 50% maternal / 50% paternal.
• Gene copies residing on X chromosomes in men are 100% maternal.
• Assuming a 50 / 50 sex distribution in any given generation, 2/3 of the X chromosome gene pool resides in women, 1/3 resides in men.
• The parental distribution of that X chromosome gene pool will be 2/3 × 1/2 + 1/3 × 1 = 2/3 maternal, and 2/3 × 1/2 = 1/3 paternal: the same distribution in F0 as in F1.
By induction (repeat the above for any number of generations), one can conclude that the current X chromosome gene pool has resided in a lineage that's by generation 2/3 female.

However, mating systems in our (long, mostly prehuman) lineage were some mix of monogamy, indiscriminate mating (as practiced by bonobos and the modern "babydaddy" system), and lek/harem/polygamous mating where older, socially dominant males are disproportionately represented (as in chimpanzees, chieftain/feudal, and modern wife/mistress(s) and serial monogamy systems). So while any given gene on the X chromosome has only spent 1/3 of its generational sequence in males, its likely that fathers were on average significantly older than mothers, so the genes probably spent more than 1/3 of their germline history in males.

I recall at least one class on genetics in my biochemistry degree curriculum, two decades ago. At that time, after a week of preliminaries on Mendelian inheritance and Punnett squares, the bulk of the course was mostly statistical methods for inferring whether genes for a genetic syndrome or disease predisposition were near other known genes on the chromosomes based on their co-occurence in family trees. Rather archaic now that we have the whole genome sequence, and can sequence individuals for known mutations cheaply.

Edited by Darryl, 24 January 2014 - 04:43 PM.


#9 Jeoshua

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Posted 24 January 2014 - 04:32 PM

The assertion that men have more genetic material due to the silencing of the second X chromosome is kind of a misunderstanding of how genetics work. Yes, men have more genes, but not all genes code for proteins that will be used by the body. Some are basically meta-instructions that can activate or silence another part of the genetic code, and that is likely how a lot of the Y chromosome works. Also there is the factor of differential genetic expression, where depending upon where in the body a cell lies, it's genetic code will have different parts activated and other parts silenced. I would bet that the cells of the ovaries have quite a lot more specialized coding that must be activated to become ovaries than the testicles have to become testicles. And the genetic makeup of the womb is certainly more complex than whatever its analogue is, in men.

Edited by Jeoshua, 24 January 2014 - 04:35 PM.


#10 xEva

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Posted 24 January 2014 - 10:18 PM

The assertion that men have more genetic material due to the silencing of the second X chromosome is kind of a misunderstanding of how genetics work. Yes, men have more genes, but not all genes code for proteins that will be used by the body. Some are basically meta-instructions that can activate or silence another part of the genetic code, and that is likely how a lot of the Y chromosome works.


Yes, Joshua, I agree. That was not the best choice of words on my part. I am aware that non-protein-coding regions are not merely "junk DNA" but play regulatory role, which I envision as a sort instruction code for the utilization of the data array itself (=genes). By saying that males have more active genes than females I meant to say that they had more active genetic material. I did not look into Y chromosome specifics and only considered its bulk as a whole.

And yes, since the default is female and males have a complete set of genetic material, then it sounds plausible that the content of Y must be suppressing the female development and direct the male.



Darryl, yes I see it now, even though I still am not too kin on your explanation. With 50-50 gender distribution, the 2/3 - 1/3 distribution of X genes is the feature of any generation, and so inductions/multiplications don't illustrate much. The 2/3 - 1/3 sequential distribution comes from the sequence of an X being passed along in a the repeated cycle: mother -> daughter -> grandson -> girl like mother again (or father ->daughter->granddaughter->boy like father again)

It is easy to see if we substitute 3 generic X chromosomes for 3 unique ones and label them A, B and C. Then instead of XX*XY mating pair we have AB*CY. Then, keeping the population constant (here is just one pair), we have these 3 consecutive generations with unique combinations of X chromosomes, (while culling all AA BB CC girls as genetically too poor and therefore non viable lol, as well as removing the duplicates like CA, CB or BA, we get this unique combinations of pairs in 3 generations:

1st generation AB CY

2nd generation AC BY

3rd generation BC AY

4th generation AB CY again, the cycle repeats itself


If we trace any of the X chromosomes above, say A, we see that every 3 generations it spends 2 in females and one in males. So yes, I see it now, thank you.

Edited by xEva, 24 January 2014 - 10:23 PM.


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#11 Consequences

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Posted 24 October 2017 - 12:24 PM

It's very ignorant to say that males handle their extra Y chromosome fine.

 

I could write a dissertation on factual life experience from the problems that extra Y chromosome caused me from birth, let alone the problems trying to fit into a society of people without extra chromosomes.

 

Furthermore you would be surprised how many autistic people have an extra chromosome but they don't get diagnosed as XXY or XYY, just the first and obvious problem - autistic.

 

I think the 1 in 1000 males have an extra Y chromosome is probably a very misleading "fact" given how much of the population is either not screened in the first place or are diagnosed with the first "syndrome" that appears.

 

For example for the first 5 years of my life I was only diagnosed as "autistic" when I have autism, asperges, and then 10 years later diagnosed with XYY when it is the causation of the former and many others.

 

For reference I am almost 7 feet tall.

 

Also for reference be careful if you have a child with high functioning XYY not to stop them learning how to defend themselves. My parents were warned that I would grow up to be a violent individual; they cut out all forms of physical violence in my life even down to not being allowed to play football or rugby or "rough and tumble" at primary school - this lead to me going to secondary school unable to take care of myself which lead to years of bullying and a mental breakdown.


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