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What is an example of a functional protein that has been observed (in real time) to have come into existence through mutations and natural selection (not through an existing one being made defective). Homologs don't count as one existed previously.

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What do you mean with "in real time"? Sequencing an organisms, adding an evolutionary pressure, sequencing again and suddenly finding a new protein? – Michael Kuhn Sep 13 '12 at 14:33
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The “real time” requirement is an incompatible criterion with the rest. It’s designed to make this question essentially unanswerable. – Konrad Rudolph Sep 13 '12 at 15:34
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Mutation of a (duplicated) existing protein is the usual way a new protein evolves. – Mechanical snail Sep 16 '12 at 22:37

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How about EWS-FLI1 and other oncofusion proteins?

One could argue that cancer progression is as close to viewing "evolution in real time" (as you say) as possible.

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From the following free review:

Here we review some of the successful strategies in creating protein diversity and the more recent progress in directed protein evolution in a wide range of scientific disciplines and its impacts in chemical, pharmaceutical, and agricultural sciences.

Quoting three examples, but the article has much more:

Directed evolution has been successfully applied to DNA polymerase for enhanced activity (233) and conversion to an efficient RNA polymerase (232, 333).

Naumann and Reznikoff (216) used directed evolution to generate a mutated Tn5 bacterial transposase that could function on transposons with mutated end binding sequences.

Organophosphate-degrading enzymes have been evolved and selected for broadened substrate specificity (53, 335). Broadened substrate specificity of a biphenyl dioxygenase has also been achieved (33, 87, 164, 291). Efforts in cleaning underground water contamination prompted the evolution of an enzyme for chlorinated ethene degradation (41).

L. Yuan, I. Kurek et al: Laboratory-directed protein evolution. In: Microbiology and molecular biology reviews : MMBR. 69, 3, September 2005, 373–392. doi:10.1128/MMBR.69.3.373-392.2005. PMID 16148303. PMC 1197809.

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Assuming that the OP was really interested in "natural selection" I guess these don't provide an answer. Of course, in the broader sense, human activity could be deemed to be an agent of natural selection. – Alan Boyd Sep 13 '12 at 14:17

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