for analyses of allele frequency differentiation across populations and allele frequency distributions , we used subsets of snps from hapmap ( public release # 21a ) which were ascertained uniformly across the genome so that the data sets are appropriate for population genetic analysis8 .
all the snps in our study are therefore uniformly ascertained as divergent sites in exactly two chromosomes of the same ancestry ( two each of either west african , north european or east asian ancestry ) and genotyped in all hapmap samples , including 120 unrelated west african chromosomes from ibadan , nigeria ( yri ) , 120 unrelated european american chromosomes from utah , usa ( of north european ancestry ; ceu ) , and 180 unrelated east asian chromosomes ( 90 han chinese from beijing , china ( chb ) and 90 japanese from tokyo , japan ( jpt ) , which we pooled for most analyses ) .
since males carry a single copy of chromosome x , the counts for chromosome x are at most 90 , 90 , and 135 ( our modeling adjusts appropriately for the sample size of every snp used in our analysis8 ) .
we removed all sites that were in hypermutable cpg dinucleotides , and determined the ancestral allele by requiring a match to both the chimpanzee and orangutan sequence8 .
first , we no longer required snp discovery in two chromosomes from the same individualfsf ; instead , we allow snps to be discovered by comparing two chromosomes , one from each of two individuals of the same ancestry , which we found generates an indistinguishable frequency distribution .
second , for the autosomal snps discovered in west africans , we used data from an african american sample ( na17109 ) who we determined had 4% european ancestry on average based on the ancestrymap software28 .
we restricted the snps used for analysis to sections of this individual 's genome where we were > 95% confident of african ancestry in both chromosomes based on an analysis with ancestrymap . in supp .
note , we present analyses showing that this procedure generates results that are indistinguishable from what is obtained by using two chromosomes from a west african .
as the african american sample ( na17109 ) used for mining snps in hapmap was male , we could not use this individual to identify sites that were different between two west african copies of chromosome x. to fill this gap , we used four west african ( yri ) samples ( na18517 , na18507 , na19240 and na19129 ) for which shotgun sequencing data was available in public databases to discover snps .
we randomly dropped sequencing reads until we had no more than two unrelated chromosomes at each site , and then used ssahasnp29 to identify 4,884 snps on chromosome x for which we could confidently identify the ancestral allele based on comparison to both chimpanzee and orangutan , for which we were able to successfully design primers , and which passed all the other filters we applied to the snps mined from hapmap .
we attempted to genotype a randomly chosen subset of 1,366 of these snps in all hapmap samples using the sequenom iplex method30 .
this resulted in 1,087 snps after removing snps with < 85% genotyping completeness , with 4 or more heterozygous genotypes in males , out of hardy - weinberg equilibrium ( p<0.01 in a statistic combined across populations ) , or monomorphic . from the 210 unrelated samples in hapmap , we filtered to 189 after dropping samples that had < 85% genotyping completeness , an excess of heterozygous genotypes in males or a deficiency of heterozygous genotypes in females compared with others from the same population , or that were one of 6 yri samples related to those used in snp discovery .
this left us with 77 yri , 82 ceu and 122 chb+jpt x chromosomes for analysis .
we obtained dna sequence reads from public databases for 5 individuals of north european ancestry ( european americans ) , 4 of east asian ancestry ( from china , japan and the united states ) , and 5 of west african ancestry ( 4 nigerians and 1 african american , whose genome was only analyzed in sections where we were > 95% confident of two african - origin chromosomes based on the ancestrymap software28 ) ( supp .
sequence reads , we aligned them to build 35 of the human reference sequence by ssahasnp29 with the settings qsnp>=40 , qneighbor>=15 , nneighbor=5 , maxneighborhooddiffs=1 , maxsnps / kb=15 .
a subset of non - overlapping sequence reads for each individual was selected at random , providing a single mosaic , haploid genome that was not biased according to the strand of dna from which a read derived . within - population sequence diversity
was estimated by only analyzing bases where there were two or more individual haploid genomes , and then counting differences by selecting two haploid genomes at random . to similarly compute between - population diversity ( supp .
table 2 ) , the individual haploid genomes of each population were combined so that at any base only one individual was represented . to estimate standard errors correcting for correlation between neighboring sites
, we used a jackknife analysis , dividing the genome into blocks of 100,000 aligned bases , and removing each block in turn.8 to estimate allele frequency differentiation across populations , we used the fst statistic as formulated in ref . 8 .
briefly , when ( i ) a snp is discovered as polymorphic in population a , and ( ii ) population a has been of effectively constant size since the split from population b , the expected value of fst is 
 e(fstauto)=(1e(a+b))/2 , where a and  b are scaled drift times . multiplying i by 4/3 , the equivalent expression for chromosome x is 
 e(fstx)=(1e4/3(a+b))/2 , thus 
 q = ln(12e(fstauto))/ln(12e(fstx))=3/4 . to test this expectation , we simulated models of history for each pair of populations and found all values to be close to  ( supp .
for analyses of allele frequency differentiation across populations and allele frequency distributions , we used subsets of snps from hapmap ( public release # 21a ) which were ascertained uniformly across the genome so that the data sets are appropriate for population genetic analysis8 .
all the snps in our study are therefore uniformly ascertained as divergent sites in exactly two chromosomes of the same ancestry ( two each of either west african , north european or east asian ancestry ) and genotyped in all hapmap samples , including 120 unrelated west african chromosomes from ibadan , nigeria ( yri ) , 120 unrelated european american chromosomes from utah , usa ( of north european ancestry ; ceu ) , and 180 unrelated east asian chromosomes ( 90 han chinese from beijing , china ( chb ) and 90 japanese from tokyo , japan ( jpt ) , which we pooled for most analyses ) .
since males carry a single copy of chromosome x , the counts for chromosome x are at most 90 , 90 , and 135 ( our modeling adjusts appropriately for the sample size of every snp used in our analysis8 ) .
we removed all sites that were in hypermutable cpg dinucleotides , and determined the ancestral allele by requiring a match to both the chimpanzee and orangutan sequence8 .
first , we no longer required snp discovery in two chromosomes from the same individualfsf ; instead , we allow snps to be discovered by comparing two chromosomes , one from each of two individuals of the same ancestry , which we found generates an indistinguishable frequency distribution .
second , for the autosomal snps discovered in west africans , we used data from an african american sample ( na17109 ) who we determined had 4% european ancestry on average based on the ancestrymap software28 .
we restricted the snps used for analysis to sections of this individual 's genome where we were > 95% confident of african ancestry in both chromosomes based on an analysis with ancestrymap . in supp .
note , we present analyses showing that this procedure generates results that are indistinguishable from what is obtained by using two chromosomes from a west african .
as the african american sample ( na17109 ) used for mining snps in hapmap was male , we could not use this individual to identify sites that were different between two west african copies of chromosome x. to fill this gap , we used four west african ( yri ) samples ( na18517 , na18507 , na19240 and na19129 ) for which shotgun sequencing data was available in public databases to discover snps .
we randomly dropped sequencing reads until we had no more than two unrelated chromosomes at each site , and then used ssahasnp29 to identify 4,884 snps on chromosome x for which we could confidently identify the ancestral allele based on comparison to both chimpanzee and orangutan , for which we were able to successfully design primers , and which passed all the other filters we applied to the snps mined from hapmap .
we attempted to genotype a randomly chosen subset of 1,366 of these snps in all hapmap samples using the sequenom iplex method30 .
this resulted in 1,087 snps after removing snps with < 85% genotyping completeness , with 4 or more heterozygous genotypes in males , out of hardy - weinberg equilibrium ( p<0.01 in a statistic combined across populations ) , or monomorphic . from the 210 unrelated samples in hapmap , we filtered to 189 after dropping samples that had < 85% genotyping completeness , an excess of heterozygous genotypes in males or a deficiency of heterozygous genotypes in females compared with others from the same population , or that were one of 6 yri samples related to those used in snp discovery .
this left us with 77 yri , 82 ceu and 122 chb+jpt x chromosomes for analysis .
we obtained dna sequence reads from public databases for 5 individuals of north european ancestry ( european americans ) , 4 of east asian ancestry ( from china , japan and the united states ) , and 5 of west african ancestry ( 4 nigerians and 1 african american , whose genome was only analyzed in sections where we were > 95% confident of two african - origin chromosomes based on the ancestrymap software28 ) ( supp .
sequence reads , we aligned them to build 35 of the human reference sequence by ssahasnp29 with the settings qsnp>=40 , qneighbor>=15 , nneighbor=5 , maxneighborhooddiffs=1 , maxsnps / kb=15 .
a subset of non - overlapping sequence reads for each individual was selected at random , providing a single mosaic , haploid genome that was not biased according to the strand of dna from which a read derived . within - population sequence diversity was estimated by only analyzing bases where there were two or more individual haploid genomes , and then counting differences by selecting two haploid genomes at random . to similarly compute between - population diversity ( supp .
table 2 ) , the individual haploid genomes of each population were combined so that at any base only one individual was represented . to estimate standard errors correcting for correlation between neighboring sites
, we used a jackknife analysis , dividing the genome into blocks of 100,000 aligned bases , and removing each block in turn.8
to estimate allele frequency differentiation across populations , we used the fst statistic as formulated in ref .
briefly , when ( i ) a snp is discovered as polymorphic in population a , and ( ii ) population a has been of effectively constant size since the split from population b , the expected value of fst is 
 e(fstauto)=(1e(a+b))/2 , where a and  b are scaled drift times .
multiplying i by 4/3 , the equivalent expression for chromosome x is 
 e(fstx)=(1e4/3(a+b))/2 , thus 
 q = ln(12e(fstauto))/ln(12e(fstx))=3/4 . to test this expectation , we simulated models of history for each pair of populations and found all values to be close to  ( supp .
 comparisons of chromosome x and the autosomes can illuminate differences in the histories of males and females as well as the forces of natural selection . 
 we compared the patterns of variation in these parts of the genome using two data sets that we assembled for this study that are both genomic in scale . 
 three independent analyses show that around the time of the dispersal of modern humans out of africa , chromosome x experienced much more genetic drift than is expected from the pattern on the autosomes . 
 this is not predicted by known episodes of demographic history , and we found no similar patterns associated with the dispersals into east asia and europe . we conclude that a gender - biased process that reduced the female effective population size , or an episode of natural selection unusually affecting chromosome x , was associated with the founding of non - african populations . 
Methods
SNP data mined from HapMap
Genotyping of SNPs in our laboratory
Sequence diversity data
Allele frequency differentiation analysis
Supplementary Material