Referee 2's review:

The manuscript submitted by Somel and co-workers describe a unique application of DNA-microarrays to gain fundamental information on human gene evolution. They assumed that those genes that are related to nutritional intervention are under higher evolutionary pressure, especialy those that are expressed in the liver. Their experimental design is based on mouse as a test animal that is fed by different diet: mouse diet, chimpanzee diet and two human diets. After determining differential gene expression patterns in mouse liver and brain and using statistical comparisons the authors claim that both the promoter sequences and the amino
acid sequences of these genes have changed between humans and chimpanzees more than random genes.

The Introduction section is too focused to evolutionary aspects but does not include several key references to basic nutrigenomic studies that first dealt with gene expression modification power of different diets in both liver (Bauer M et al. Linking nutrition to genomics. Biol Chem. 2004 Jul;385(7):593-6.) and brain (Kitajka K et al. Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression. Proc Natl Acad Sci U S A. 2004 Jul 27;101:10931-6.). Nutrigenomics in general should be mentioned in general in a separate paragraph in the Introduction section.

The reviewer understand that the main message of the paper is to show statistically significant correlation between genes and promoter elements, comparing the numbers itself cannot be always applied to have conclusions to evolutionary processes. The authors found that the effects of human diets were found to be significantly different from that of a chimpanzee diet in the liver, but not in the brain, bioinformatics analysis of diet-influenced brain specific genes could reveal important functional differences related to human evolution. These data (specific genes) should have been also analyzed in the context of their function not only deal with statistical results. In the opinion of the reviewer this is the only weakness of the paper, that should be addressed to improve the manuscript.

However we could gain some interesting informaion on how McDonald's fast food affect relative gene expression patterns, I think this has small relevance to evolutionary pressure when we think in an evolutionary time scale (possible access to these kinds of diet in the past).

The reviewer would be interested how dietary gene expression changes and statistical results would change (with the conlcusion of the „unaffected" brain specific genes) if the authors would apply longer period of intervention time. From the literature it is well known that for dietary brain-specific gene expression changes more than 6 (even longer) weeks are needed (see REF above). A sentence dealing with this possible factor should be mentioned in the Discussion section.

Some minor suggestions:

In the Results section, paragraph 3, it should ease the understanding of the functional categories of the genes if the authors refer to Tabel S5 (they refer to this only in the Methods section).

In summary the manuscript is very well written and organized, the figures and tables (including the supplemented ones) can be understood well and useful in supporting of the statements. Because of the unique methodological and statistical approach that revealed correlation between diet-induced gene activity changes and evolutionary processes, and because these data suggest new basic knowledge on environmental (diet) pressure on gene evolution I think that the manuscript will be of great interest to the scientific community.

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.