I ran into similar problems with a combinaison of Gens and Irfanview on my first couple of Sonic CD maps.
See, my desktop is always set to 32 bits color, but Gens always switches it to 16 bits while it runs. So far so good. I ran into a problem when I started assembling screenshots while the emulator was running because whenever I copied a screenshot from Irfanview, it would copy to to clipboard the image being displayed (now in 16 bits) instead of the actual data from the file which was 24 bits. Almost all the colors thus ended up having their individual color channel shifted by a few unit, so everything I would paste on the map canvas while Gens was open would have different color values that wouldn't be apparent to the naked eye but would cause a lot of problems when trying to alter pixels of a specific color value across the whole map.
Paint however remembered the real RGB value of the pixels already there even though the colors displayed might be different because of the 16 bits setting of the desktop. Let's say that I would have a big blue square. The left half of this square is made of (0,0,255) blue while the right half is made of (0,0,252) blue. But because of the 16 bits mode, everything is being displayed as (0,0,252) even though Paint *knows* that internally, both areas have different colors. So, while Gens was still running and causing everything without me suspecting foul play, I would use the Fill tool to try and recolor the whole square only to see that only half of it changed. And when I copied the whole thing in Irfanview to check the RGB values of pixels on both sides, it would give the value of what was displayed which was all (0,0,252) everywhere. All in all, I ended up tracking down the problem, then spent an hour or two recoloring all the problematic pixels on the two maps in question, and now always close Gens once the screenshots have been taken before doing any real assembly in Paint.
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"With the first link, the chain is forged. The first speech censored, the first thought forbidden, the first freedom denied, chains us all irrevocably." [...] The first time any man's freedom is trodden on, we're all damaged. - Captain Jean-Luc Picard
B*tch, meet reality. Reality, meet b*tch. - Me