|How not to splice a tape courtesy of FSAudio|
They aren't second nature, and there are no hard-and-fast rules for how to use commas. You're supposed to use them in natural pauses in sentences, but different people will inflect their sentences differently. If you examine my above sentences, you'll see that I use commas to separate out independent clauses, but I learned to use commas long before I knew what an independent clause is.
The best way to learn how to use commas is to write, get it wrong, and learn. Someone will have to point out the commas in the wrong places, or that you don't use them enough, or that it sounds like Stevie from Malcolm in the Middle is narrating your words. You can try to spot your own comma issues by reading aloud, but, if you don't know the first thing about commas in the first place, it's unlikely to help you. If you exaggerate the pauses cued by commas as you read, you may find misplaced commas, but it's no guarantee.
The most preventable comma issue, and therefore the one you can learn without making mistakes first is that of comma splices. A comma splice is when two sentences are blended together using a comma instead of a period.
A basic sentence is composed of a subject and verb. Sentences can be joined together with a conjunction, and they're often much more complicated than a simple subject and verb. Further complicating the issue is gerunds, which is what you get from verbing a noun.
But, generally speaking, if a sentence has two verbs, it's a run-on. If those two distinct sentences are separated by a comma, the fix is as easy as changing the comma to a full-stop or adding a conjunction to blend the sentences seamlessly together.
I'd say that not having these down will get you rejected outright, but I'd be lying. I've read two professionally published books with comma splices lately. One of them may have been on purpose, but it still bothered me. Knowing what to do with commas, though, will allow editors to look at fixing other parts of your manuscript, instead of having to linger over your comma issues. You'll be doing yourself a favor.