A letter in this week's Science by Thomas Erren and colleagues (2007) questions the whole-genome approach to sequencing Neandertals:
However, although such comparisons are of interest, it is not the static genome but rather the dynamic proteome that determines the phenotype of an organism. Salient examples include the caterpillar and the tadpole, which share genomes with the butterfly and frog, respectively, but which have very different proteomes making them into very different organisms. Thus, rather than performing untargeted comparisons of sizable genomes, we suggest that it might be more useful to address this question using a standard hypothesis-driven approach. One such avenue might be the "fat utilization" hypothesis, which holds that the key mutations that differentiate us from Neanderthals and great apes are in the genes coding for proteins regulating fat metabolism, in particular, those regulating the phospholipids in brain synapses (3, 4). A specific search for variations in genomic DNA or gene expression related to lipid biochemistry and metabolism could be carried out.
Rubin and Noonan (2007) respond effectively to the letter (same doi as the letter above). Their answer is essentially that the whole-genome approach will be able to find evidence for evolution in particular gene systems like this; since the genome is a finite set there is no reason not to sequence the whole thing.
It's not that meaningful an exchange. In particular, I think these theories about the "one critical change" leading to modern humans are mostly sterile. I would suspect that many people will be surprised at the result from the whole-genome analysis of Neandertals, and it will take a long time to interpret.
I also thought I would plug my previous summary of the Neandertal genome story. If you're interested in the Neandertal genome, you may want to see my FAQ, in which I explain the genomic approach and its strengths and weaknesses.