If this thread helps us in vocalizing and distilling the design decisions which lead us to consider a physical layout "better" than another then I think it's already worth it. Theoretically we could even make a flow chart that leads to an optimal layout through a number of clear decisions.
Discussions are really enlightening (I read a really good suggestion here on why the number layer should be on the left hand for mouse usage, I still don't know how I'll take this into account) but at the end of the day, I agree on the fact that there's definitively no universal answer. People have too different usages and preferences. I mean, even for layouts: dvorak is *based* on the idea that alternating hands is good. I far prefer rolls to strict alternating in several cases.
The flow chart is an interesting idea. It could be nice to make a list of different solutions, and try to put them in a tree based on their differences, and what idea made its creator choose one path against another. I may try to do this one day

That's an interesting idea, keeping only some of the more common accents handy. Probably won't tho, exactly because of your earlier French person vs. programmer analogy. I'm a programmer/researcher too + I hang out at places like this in my free time so English will have to be the main consideration.
I'm french and programmer too (not doing much research currently, but I used to) and while I moved some accentuated keys in layers, I kept é and è on base layer. The first one (é) is more common in french than half the letters without accents, so it doesn't make sense to put it on a layer.
I'm more and more thinking about moving è to a layer, too, but at the same time, I think about promoting à instead. More common, and é/à can actually be first letters of sentences, so capitals is common on those. I would get rid of layer switch + caps combo (well, except for ç, but that's rare enough).
Also, I have quite a few colleagues who stopped using accents in their informal Hungarian university/chat communications because they program on a standard US ISO layout so I might not even miss them that much.
I'm not sure how it is in hungarian, but I HATE this in french. I'm not even that fond of the rule where you don't put accents on caps (mostly because it's actually impossible to get a capital-é with default layout, go figure!) I won't say I will not deal with people doing this, but still a step in that direction ^_^
My main goal with transitioning to a custom layout is to avoid any keys that require more than 1 unit of stretching. The number row is 2 steps from the home row and I've always hated it. I usually just used the numpad but the extra hand movement is another topic altogether... So yeah, I'm trying to avoid uncomfortable keys, which would naturally lead to a numpad layer. As for the symbols on the numrow, they are already shifted, so why not have that "shift" be a symbol layer and access them in even better positions?
I did the same... unless I'm mistaken, I can type anything with the 3 central rows (well, except the japanese layer, but that's a special case)
I'm still happy to have the 4th and 5th rows. They act as shortcuts... it's easier to use them in some cases rather than switching to a different layer.
I found the 2nd bottom row to be a nice fit to function keys. You don't use them while typing, but having them in layer isn't great (even more so because you'll want the most accessible layers to be caps, symbols, numbers, arrows...). That's because I use a lot of function keys with modifiers, and often several modifiers. Think Alt-Shift-F4. Add a layer switch modifier on top of that and that can become hellish. Besides, that's the kind of keys that I sometimes use in conjunction with mouse...
For the 2nd top row, I still enjoy having some symbols there. I think a vertical +2 for forefinger/middle finger can be more comfortable than a layer (or even +1 vertical +1 horizontal). I was unable to find room for - or \ for example on the base layer 3rows, and for LaTeX, honestly, I want \ on a direct key. It actually works better if the staggering is NOT aggressive, Ergodox-style (I actually prefer a small staggering and some "depth" adjustments: middle fingers keys being lower (with respect to the direction of typing), like on Logitech Wave.)
That being said, again, I'm french, and I'm used to *symbols* on the top row, not numbers.
My advice would be: consider not getting rid too early of physical keys/rows, design your layout on 3 rows with unused keys, and see if it suits you or if unused keys can be put to some use. Same for pinkies columns (though if you want aggressive tenting, there IS an argument for getting rid of external column)
It'll take years to refine your perfect setup, in any case.
I think you should not make it too difficult for yourself to type on it. If you would need to move the keyboard between computers then you may not be able to have a custom keymap on the host.
That's actually a good question. I'm more and more using my own layout (that works on both Ergodox-like layout and QWERTY layout, and can be install on Windows, both conditions being harsh) but I still need to be able to type on normal layouts. Sometimes, it feels a bit akward, but not enough to get stuck with a layout I'm not fond with.
I suppose that you will have all modifiers on thumbs, and that would only be suitable for at most two modifiers at once because you have only two thumbs.
With good keys, you can always chord, but I took a different approach: to have two modifiers on each side, for example, I use 3 buttons on each side, one being both modifiers: for example, [alt], [shift], and [alt+shift]
It works really well.
You can also add modifiers to some non-thumb keys on some layers (press alt and there's a shift you can press with pinkies or indexes). In some cases, it works better, in others it's not as good.