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Referee comments: Referee 2 (John Whitfield)

Posted by PLOS_ONE_Group on 04 Apr 2008 at 16:25 GMT

Referee 2's review (John Whitfield):

This paper describes allelic and haplotype frequencies for ADH variants in multiple populations from East Asia, and uses the data to infer the presence of selective pressures on ADH1B in some populations (defined by geographic and ethnic criteria) and not others. As such, the information and conclusions are of interest to a wide range of people - population geneticists, alcohol researchers, anthropologists, and indeed anyone interested in the history or prehistory of humans.

My major comment on the paper as it stands is that is not easily comprehensible by the range of people who may read it, and specifically that the method for detecting selection - its basis, strengths and possible weaknesses - is not explained. A paragraph in the Introduction explaining the basis of the Extended Haplotype Homozygosity (EHH) and Relative Extended Haplotype Homozygosity (REHH) methods would be advantageous. Even an earlier and more prominent citation of references 77-79 would help; the explanation by Voight et al (78) that "The classic signal of strong directional selection is that because the favored allele increases in frequency very fast, it tends to sit on an unusually long haplotype of low diversity .... chromosomes that do not carry the selected allele have levels of diversity and LD that are more typical of the genome as a whole" makes the basis of the method much clearer.

Other points:

1. The statistic Fst is introduced on page 7 without definition or explanation
2. Again on page 7, the authors state that 'The Fst values of the Arg47His variant and the promoter variant of ADH1B are the highest", but SNPs 15 and 30 have higher values than SNP 11 (the promoter polymorphism)
3. On page 12-13 it is suggested that SNP 11 (rs3811801) might affect ADH1B expression - is there any information on whether it does?

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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.