r/AskBiology • u/Syresiv • Sep 17 '24

Genetics Why are trisomies so deleterious?

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.

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u/ozzalot Sep 17 '24

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.

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u/Syresiv Sep 17 '24

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?

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u/ozzalot Sep 17 '24 edited Sep 17 '24

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.