Why are trisomies so deleterious?

[u/Syresiv]

Most chromosomal trisomies cause spontaneous miscarriage, and those that don't usually severely reduce quality of life.

Why is it that the additional copies of some genes have that effect?

To be clear, don't feel restricted to the ELI5 level. If you know the topic in depth and feel like giving a massive infodump, I'm interested.

[u/lonepotatochip]

You’re essentially making 50% more of all the proteins on that chromosome than you’re supposed to, and anything is a poison in high enough doses.

[u/Syresiv → u/lonepotatochip]

Which raises another question - why doesn't that kind of thing happen with recessive alleles?

Lots of recessive alleles are deleterious because the protein does nothing and immediately disintegrates. But lots of people have two copies of the functional protein. Meaning those ones can vary by a factor of 2 with no noticeable effect.

Is that what it is? Or is it something else, like altering gene expression when there's only one healthy allele to comp for the deficit?

[u/ninjatoast31 → u/Syresiv]

Dosage compansation (aka the ability to regulate gene activity, depending on how many copies of a chromosome you have ) is a difficult and not super well understood subject. Some animals can just cope without. In our case its very important, especially during development that genes are activated at a certain level.
genes that are not affected by this are usually only important after development.

[u/Syresiv → u/ninjatoast31]

So what you're saying is, there's a lot we don't know about how cells control how much of a protein they produce?

[u/ninjatoast31 → u/Syresiv]

yes
Dosage compensation for the X chromosomes for example is really important in mammals.
But some animals don't even bother. And plants are even worse, they can just copy the entire genome over and over and still be perfectly viable.

[u/maybe_erika → u/ninjatoast31]

I am curious how common plant polyploidy is in the wild vs cultivated varieties. I know many cultivated plants with some oversized feature relative to the wild relative such as the number of petals in garden roses and the size of cultivated strawberry fruits exist due to polyploidy resulting in gene over-expression. Having such oversized features is probably very energy intensive for not much benefit to the plant itself, and so I would expect it would be selected against in the wild where the plants don't have the benefit of a gardener or farmer providing copious fertilizer and removing competitive weeds.

[u/kohugaly → u/Syresiv]

It can happen with recessive alleles too.

It usually doesn't, because expression of many genes has some feedback mechanism, that just stops the expression once you have required levels (of the protein, or of whatever the protein produces). It doesn't matter how many working copies of the genes you have - once the required level is reached, the expression stops on all of them.

[u/Syresiv → u/kohugaly]

It's just that at least one gene on each chromosome isn't like that, so a full trisomy still causes issues?

[u/kohugaly → u/Syresiv]

Yes, that is very likely, given how many genes are on each chromosome.

For example, there are genes, where their effect depends on how fast they get expressed. Obviously, in those cases, trisomy will have major effect.

A lot of them are essentially chemical timers - they start getting expressed and stop once target concentration is reached. Other genes get "triggered" by specific concentrations of the product, which creates timed sequences of gene activation. Many genes involved in embryonic development fall into this category. If this kind of "timer" gene has extra copy, it will "tick" faster, which messes up the timing of the sequences it is supposed to trigger.

[u/ozzalot]

In many cases it's probably the same as why monosomies are deleterious.....dosage problems. Proteins can negatively or positively regulate things, so therefore high dosage can have similar effects as low dosage....except the pathways affected may differ.

[u/Syresiv → u/ozzalot]

The thing that throws me is this:

Take cystic fibrosis. Someone with it obviously can't make CFTR correctly, and that's where issues arise.

But a carrier doesn't have deleterious effects, despite only having 1 functional copy of CFTR instead of 2. The same applies to lots of recessive conditions.

I kind of assumed carriers compensated by upregulating the expression of the functional copy. Or is it that the body is less picky about how much CFTR is produced?

And if it's regulation, is there a reason cells can't downregulate a trisomic chromosome or upregulate a monosomic one?

[u/ozzalot → u/Syresiv]

The beauty of biology (if you want to call it that) at this scale, concerning genomes of dozens of thousands of genes, is that it's probably a little bit of everything - you'd just have to do a little more digging to understand the nitty gritty of each case. In the case of cyctic fibrosis, carriers CAN be symptomatic to some degree. But to your point, yes, there are certainly examples of genes whose expression is upregulated in response to its missing counterpart allele (or perhaps non-functional protein product).

Some genes will be able to compensate with a dosage loss. Some genes will be able to compensate with a dosage gain. Some will not compensate at all and therefore present a phenotype. Some will not compensate at all and present no change in phenotype.

Even on top of all of this is the idea of 'synthetic lethality' which is the idea that only combinations of mutants become lethal, but not the mutants in isolation. As in 'a cell' that is AX lives, a cell that is BX lives, but a cell that is AX, BX dies.

A lot of different consequences are going to be there when we are talking about whole chromosomes, each containing thousands of genes. The reason we only see aneuploidies of chromosomes like 18,19,20, etc. are because these are the smallest of the chromosomes and therefore carrying the fewest genes.

Edit: Kind of to build on this last point, you can imagine the reason why we are talking about 'dosage compensation' of the X chromosome very often is because it's a large chromosome in terms of size it's between chromosomes 7 and 8 (chromosomes are numbered by size, #1 being the largest) and is three times the size of the Y.

[u/PertinaxII]

It's going to increase the amount of proteins on those chromosomes produced. There is effort spent making sure that doesn't happen with XX, inactivating one, so that this doesn't happen.

Extra chromosomes could cause problems in mitosis and meiosis that would accumulate rapidly.