Why does X-inactivation happen?

Submitted by NeedleworkerCapital8 t3_111lkt7 in askscience

To my limited understanding of this process, early during embryonic development there is a random inactivation of an X chromosome out of the pair that a female inherits. My question is: Why does this inactivation occur? We also inherit a pair of autosomes so why isn't there inactivation happening to one of them and this is only specific to the X pair, i saw some answers that say "So females dont have double the proteins coded by the X pair" but wouldn't allele dominance solve that? Is it way more complex than that?

My understanding is very elementary so i hope you bear with me, thanks in advance.

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SignalDifficult5061 t1_j8gunf0 wrote

Dosage compensation. Autosomes are always at two copies, the X chromosome can be one or two. "Bad" recessive genes on an autosome can be masked to varying degrees by good copies. It makes more sense to have two copies rather than one for the most part for everything with paired chromosomes apparently.

The "dosage" for a XY chromsome carrier and XX chromosome carrier is kept even by an X chromosome inactivation.

There are other ways around this that could have evolved, but this is what we have.

Bacteria often have multiple copies of their genome, which can vary wildly depending on growth state and other things, so they have other compensatory systems.

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To be nit picky, there is a pseudo-autosomal portion of the Y chromosome, and there are a small amount of genes that aren't inactivated on the "inactive" X.

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NeedleworkerCapital8 OP t1_j8h2nel wrote

Thank you a lot for responding, however i want to know, what dose are you talking about when you say "dosage"?

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SignalDifficult5061 t1_j8h5stm wrote

All things being equal (with no regulation etc.) two copies of a gene are going to make twice as many mRNA transcripts and twice as many proteins as a single copy.

So gene dosage essentially.

Having too many copies can be damaging or lethal to an organism, especially in complex delicate situations during development.

This is a gross oversimplification (and not something that actually happens), but what if your brain was trying to make itself two times bigger than what your skull could contain?

You can imagine all sorts of processes going out of whack in a single cell, let alone when they have to interact in complicated ways.

There are other ways evolution could have dealt with it, but we have evolved to have around two functional copies of a gene on the autosomes (with a few recessive completely non-functional genes here are there), but that is quite a bit different than having a two fold difference across the entire X- chromosome.

Once the system we have evolved, it would be very difficult (practically impossible) to change the regulation of almost every single gene on the X-chromosomes, let alone change the regulatory scheme of every genes on the autosomes.

So yeah it is conceptually weird, but the barriers to doing something different in evolutionary terms are too high or too unlikely for it to have occurred in humans. Biology does not have to make sense from the standpoint of how a reasonable person might design a thing.

Even in tightly regulated genes, it can take more energy to regulate for two copies than one, which would be exacerbated across the entire X-chromosome. Again, we have evolved in such a manner that we are regulating our two copies of autosomal genes appropriately, which is evident by the fact that we are here.

Edit: this is over generalized for all animals. There are some other methods of dosage compensation in animals. Drosophila just doubles expression on an X chromsome, instead of inactivating one. There are some other methods of dosage compensation in other animals, especially those with different type of sex chromosomes.

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NeedleworkerCapital8 OP t1_j8h85s7 wrote

Thank you a lot once again, you explained it clearly for me and i hope i understood it right, but i have a question still if you can, shouldn't allele dominance solve the issue? As in, we have an allele of each gene encoded in each X chromosome, if each gene has a dominant allele that is expressed and a regressive one which is not, wouldn't that mean that the total expressed wouldn't surpass the genes of one X chromosome? Or is co-dominance going to create enough duplicates for it to be troublesome, i know allele dominance is way more complex than that but I'm wondering where I'm being wrong.

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Luenkel t1_j8i1lzu wrote

Dominance has nothing to do with which genes are expressed. It's not about one allele "recognizing" and shutting off the other. Generally speaking for a gene on an autosomal chromosome, both alleles will be expressed. Dominance is a question of whether the effect of one allele can mask the effect of another. So for example let's say you had an allele that produces a protein which is toxic in some way and thereby causes a disease. Then even in a heterozygous organism the single copy of this toxic allele might be enough to produce the diseased phenotype and therefore that allele would be classified as dominant. The healthy version of the protein would still be present in cells but that doesn't matter. I recommend you read the "molecular mechanism" section on the wikipedia article on dominance for more examples and details.

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NeedleworkerCapital8 OP t1_j8iswr0 wrote

I understand allele dominance clearer now, it makes more sense this way, Thanks a lot

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agate_ t1_j8igwtp wrote

Re “dosage compensation”, is it generally true that more copies of a gene means more gene expression? Aren’t most genes regulated by homeostatic feedback systems?

And what about the many, many plant species that get along just fine with duplicates or triplicates of their entire genome?

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CrateDane t1_j8ix0fy wrote

>Re “dosage compensation”, is it generally true that more copies of a gene means more gene expression?

Yes, it is true to varying extents.

Cancer cells often have genetic errors adding extra copies of oncogenes, which helps boost their growth etc. That wouldn't work if everything just got compensated back to baseline.

>Aren’t most genes regulated by homeostatic feedback systems?

There is a fair bit of that, but it wouldn't necessarily compensate fully. It also wouldn't be uniform, so some genes would have relatively more expression compared to others, which itself could have problematic effects.

>And what about the many, many plant species that get along just fine with duplicates or triplicates of their entire genome?

Well, at least those don't skew the relative dosage of different genes. It's still usually lethal in animals though, so it's an interesting question.

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SignalDifficult5061 t1_j8jramu wrote

nice answers!

I'll just that extra copies of a single autosome (so 3) generally end in embryonic lethality, except for Down Syndrome and a few others very rarely. So dosage is generally important for whole chromosomes.

Extra X chromosomes lead to relatively mild phenotypes vs extra single autosomes, which may relate to X inactivation.

Total genome duplication isn't limited to just plants, and some frogs have up to 12 sets. I don't know a ton about that, other than that often many of those chromosomes aren't fully functional.

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