My strategy on my Let's Split and now Iris is that I select layers by holding down left hand Homerow keys, then type with my right hand. Holding f turns my right side into Vim style arrows. Holding s turns it into a number pad, and holding s turns it into a symbol pad. Modifiers are where you'd expect but holding them types my most commonly used symbols {} under Options, Esc and Enter under Commands, <> under Hypers. Control is where you'd expect caps lock and ' but tapping those are " and ' respectively.

So what I'm saying is use home row hold/tap just for layer selects that will only affect the other hand, and use hold/tap modifiers for programming symbols.