Reviewer 1's Review (David G Smith)

“The authors use an imaginative approach to evaluate inferences already made using mtDNA and Y-chromosome haplotype data (but without a sex bias) regarding the origins of H. sapiens, the time of its dispersal from Africa and a series of founder effects experienced by populations expanding further eastward through Eurasia toward the Americas. A 47 Kb haplotype block on chromosome X defined by four STRs linked to an Alu insertion that is polymorphic in most populations in the CEPH-HGDP panel (except, they argue, in the Americas) is analysed. LD analysis suggests the block is in (almost?) complete linkage disequilibrium hence suitable for analysis as a single polymorphic gene. Haplotypes for this “gene” are constructed for almost all male members of the CEPH panel (for 51 of the 52 populations) and reported for geographic regions.

The AMOVA, showed low levels of population structure except in Oceania and Native America, and the distribution of haplotypes revealed a much higher level of haplotype diversity within, than outside, Africa, continuously decreasing diversity moving eastward toward the Americas and sharing of haplotypes predominantly among populations outside Africa.

Median joining networks were employed to identify several hypothetical founding haplotypes outside Africa and coalescent analysis was conducted using the program BATWING to estimate the time of TMRCA and age of the Alu insertion in the haplotype block analyzed. The results of the above analyses were consistent with those based on previous studies using predominantly mtDNA and Y-chromosome data. They illustrate the value in using the human genome map to select haplotype blocks in the nuclear genome that are useful for the study of population history that do not reflect the sex biases of mtDNA and Y-chromosome studies. I recommend publication of this paper with only minor revisions. I suggest the authors consider the relatively minor concerns expressed below in their revisions:

1. African haplotypes in the haplotype networks fell at the periphery of the network, as would be expected of highly derived haplotypes. This makes no sense to me. The authors seem to try to explain this at the bottom of page 14 by arguing that the populations in the CEPH panel reflect only a small portion of the haplotype diversity in Africa. First, I don’t understand how this could explain the peripheral position of African haplotypes in the networks. The authors need to make this clearer. Second, are there other possible explanations for this perplexing outcome, such as homoplasy, the subsequent extinction of many of the founding haplotypes outside (but not inside) Africa, or incomplete linkage disequilibrium, that might contribute to this finding?

2. The authors don’t explain how coalescence is calibrated to time to estimate the 182,000 year old age of TMRCA and the 94,400 year old age of the Alu insertion. I assume this is inherent in BATWING, but most readers will not be familiar with the details of this program.

3. Some reference to the fact that the haplotype block analyzed, just like the mtDNA genome and Y-chromosome non-recombining regions, is only one gene with its own history. This is, in fact, the value of doing this sort of thing- we can confirm inferences by looking at multiple “genes”

…

8. The authors conduct several different tests, none of which provides unequivocal evidence for non-zero recombination, but conclude that the haplotype block studied experiences absolute linkage disequilibrium.
Rejecting the null hypothesis of random recombination, as the authors have done, doesn’t prove complete linkage disequilibrium. Moreover, there is no necessary correlation between p values and the level of recombination, as is implied on line 13 of page 8.”

N.B. These are the general comments made by the reviewer when reviewing this paper in light of which the manuscript was revised. Specific points addressed during revision of the paper are not shown.