Characterization of X-Linked SNP genotypic variation in globally distributed human populations
© Casto et al.; licensee BioMed Central Ltd. 2010
Received: 15 September 2009
Accepted: 28 January 2010
Published: 28 January 2010
The transmission pattern of the human X chromosome reduces its population size relative to the autosomes, subjects it to disproportionate influence by female demography, and leaves X-linked mutations exposed to selection in males. As a result, the analysis of X-linked genomic variation can provide insights into the influence of demography and selection on the human genome. Here we characterize the genomic variation represented by 16,297 X-linked SNPs genotyped in the CEPH human genome diversity project samples.
We found that X chromosomes tend to be more differentiated between human populations than autosomes, with several notable exceptions. Comparisons between genetically distant populations also showed an excess of X-linked SNPs with large allele frequency differences. Combining information about these SNPs with results from tests designed to detect selective sweeps, we identified two regions that were clear outliers from the rest of the X chromosome for haplotype structure and allele frequency distribution. We were also able to more precisely define the geographical extent of some previously described X-linked selective sweeps.
The relationship between male and female demographic histories is likely to be complex as evidence supporting different conclusions can be found in the same dataset. Although demography may have contributed to the excess of SNPs with large allele frequency differences observed on the X chromosome, we believe that selection is at least partially responsible. Finally, our results reveal the geographical complexities of selective sweeps on the X chromosome and argue for the use of diverse populations in studies of selection.
In humans, females typically carry two X chromosomes while males are haploid for almost all X-linked loci, complementing their one X chromosome with the smaller Y chromosome. This relatively small alteration to the standard of simple diploidy followed by all 22 autosomes has profound consequences for X-linked markers relative to their autosomal counterparts. Even under conditions of gender equality with respect to migration and population size, the smaller effective population size of the X chromosome means that drift may have a more profound influence upon it compared to the autosomes. Some repercussions of this are suggested by the results of Rosenberg et al.  and Ramachandran et al. , who observed that X chromosomes are generally more differentiated among human populations than are autosomes. On a worldwide scale, drift has been invoked to explain why approximately 15% of the genetic variation observed at X chromosomal single nucleotide polymorphisms (SNPs) is between populations for the 51 Centre D'etude du Polymorphism Humaine-Human Genome Diversity Project (CEPH-HGDP) populations while that figure is only 10% for the autosomes . This observation raises the possibility that X-linked markers may be superior to autosomal ones for distinguishing closely related populations. In addition, each X chromosome spends two-thirds of its time carried by a female. This means that X-linked markers are disproportionately influenced by female demography, making them useful for detecting differences in the demographies of the two genders. Indeed, many recent studies have found evidence on the X chromosome for skewed female to male population size and migration rate ratios [4–6], suggesting that such differences may be the norm rather than the exception in human history.
Just as the interaction between demographic factors and genetic variation is special for the X chromosome, so too is the interaction between selective forces and X-linked genetic variation. For the autosomes, a recessive mutation must become sufficiently common to be present in homozygotes before selection can act upon it; this is not the case for the X chromosome, where recessive mutations are always exposed to selection in males. Consequently, given otherwise equal conditions, recessive beneficial mutations arising on the X chromosome are more likely to go to fixation than those arising on the autosomes, while recessive, deleterious mutations are more likely to be lost . The X chromosome's haploid state in males and its smaller overall effective population size also mean that selection-driven fixation or loss of non-neutral X-linked alleles proceeds more rapidly than comparable processes on the autosomes, regardless of the initial frequency of the selected allele . While it remains unclear how important recessive, non-neutral mutations are to human adaptation and to evolution in general, there is some evidence that positive selection acting on recessive, beneficial mutations has been important in shaping patterns of X-linked genetic variation in humans .
Given the special features of the X chromosome and of its interactions with the forces that influence human genetic variation, the analysis of patterns of X-linked genetic variation both independently and in comparison to autosomal patterns has the potential to reveal features of large genome-wide genotypic datasets that cannot be detected using autosomal markers alone. Here we use a number of methods to characterize the data represented by the approximately 16,000 X-linked SNPs typed as part of a genome-wide panel in the 51 globally distributed CEPH-HGDP populations. We begin by examining the population structure underlying variation on the X chromosome. We then use Fst values and pairwise allele frequency differences to examine population differentiation and explore what the results of these analyses indicate about past demographic patterns. Finally, we scan the X chromosome for haplotype structure consistent with the influence of selection. We finish by discussing two regions we identified as being clear outliers from the rest of the chromosome with respect to SNP allele frequency distribution and linkage disequilibrium patterns.
Results and discussion
The dataset described previously by Li et al.  consists of 656,995 biallelic SNPs genotyped in 938 individuals from 51 populations (in this study we consider all Bantu individuals as one population and all Han Chinese individuals as one population); 16,297 of these SNPs are located within the non-pseudoautosomal region of the X chromosome. As the CEPH-HGDP sample set includes 383 females and 615 males, this dataset contains information from 1,261 X chromosomes. The non-pseudoautosomal region of the X chromosome consists of approximately 148 Mb of genome sequence, yielding a marker density of about 22 SNPs per 200 kb. This is about half the marker density of the autosomal SNPs in this dataset (reported by Pickrell et al.  to be 40/200 kb), which is expected given that a tag SNP strategy was used to select markers for the Illumnia 650K chip and that the average recombination rate on the X chromosome is about 60% of the average autosomal rate . The genotypes were phased using the program fastPHASE ; for the X chromosome, known haplotypes from male chromosomes were also used in phasing the female chromosomes.
AMOVA results for 14 groupings of the Human Genome Diversity Project populations
Variance components (95% confidence intervals)
Number of regions
Number of populations
Among populations within regions
Among populations within regions
Pairwise allele frequency differences
Results of the delta analysis for three population comparisons
Delta > 0.9
Delta > 0.9
Delta > 0.9
Delta > 0.8
Overall, we observed that there were proportionally more high-delta SNPs on the X chromosome than on the autosomes for population pairs with one African and one non-African population (25 out of 16,297 compared to 62 out of 640,698 and 159 out of 16,297 compared to 265 out of 640,698 for the Yoruba-French and Yoruba-Han comparisons, respectively; Table 2). For the French-Han comparison, this excess of high-delta SNPs on the X chromosome was not observed. This apparent disparity between the three population pairs could be explained by a female-specific bottleneck during the out of Africa migrations as recently suggested by Keinan et al. . When there are equal numbers of males and females, the X chromosome is more heavily influenced by drift than the autosomes due to its smaller population size; this effect is exaggerated when there are fewer females than males. But is drift alone sufficient to explain the excess X-linked high-delta SNPs found for the Yoruba-Han and Yoruba-French pairs? To address this question, we utilized an equation developed by Segurel et al.  that expresses the expected relationship between X-linked and autosomal Fst values in terms of Nf/N, the female proportion of the effective population size, and mf/m, the female proportion of the total migration rate. This equation was derived from known relationships between Fst values and male and female migration rates and effective population sizes under the infinite island model with populations of equal and constant size. We used the equation to obtain expected delta values for the X-linked SNPs from the observed autosomal delta values. If autosomal and X-linked markers differed collectively only by the relative effects of drift, transformed autosomal delta values (expected X-linked values) should not differ statistically from observed X-linked values. We applied this transformation to our three lists of autosomal delta values varying Nf/N and mf/m from 0.01 to 0.99. As the female portion of the effective population size and migration rate in humans has likely varied widely across time and geographical distance, we wanted to test across all possible values of Nf/N and mf/m, including 'Nf/N, mf/m' pairs where Nf/N < 0.5, as such pairs represent female specific bottlenecks (that is, more than half of the population is male).
Characteristics of X-chromosomal high-delta SNPs
Delta > 0.9
Delta > 0.9
Delta > 0.9
Delta > 0.8
High derived frequency
(in second population)
For each of the X chromosomal high-delta SNPs, we determined which allele was derived and which ancestral using information from two chimpanzees that were genotyped along with the HGDP samples in Li et al.  and information from the NCBI website . We were able to determine the ancestral state for the majority of the autosomal and X-linked high-delta SNPs. For the Yoruba-French comparison, 3 out of 25 (12%) high-delta SNPs had a high derived frequency in the Yorubans, and for the Yoruba-Han comparison, 26 out of 159 (16.4%) high-delta SNPs had a high derived frequency in the Yorubans. For the autosomes, we found that only 5 out of 58 (8.6%) high-delta SNPs had a high derived allele frequency in Africa in the Yoruba-French comparison; that figure was 18 out of 247 (7.3%) in the Yoruba-Han comparison (Table 3). The percentage of X-linked high-delta SNPs with high derived allele frequency in Africa significantly exceeds (chi square test, P < 0.001) that for the autosomes in the Yoruba-Han comparison; this could be explained by a higher incidence of hitchhiking on the X chromosome compared to the autosomes. An alternative, and intriguing, possibility is that the X chromosome has been affected by a disproportionate number of selective sweeps or drift events (for example, bottlenecks) involving derived alleles in Africa. Looking back to our identification of genic and non-genic high-delta SNPs, we found some evidence that selection may indeed be a player in this observation. Recall that for the Yoruba-Han comparison (when we excluded the one exceptional high-delta region, 65.5 to 67 Mb), 44.4% of all high-delta SNPs were in genic regions. If we take only those high-delta SNPs that have high derived allele frequency in Africa, this increases to 50%. Similarly, all three high-delta SNPs from the Yoruba-French comparison with high derived frequency in the Yorubans are found in genes.
Tests of selection (iHS, CLR, XP-EHH)
Figure 4 displays all of the 61 400-kb X chromosome regions that contain either a high-delta SNP in the Yoruba-French or Yoruba-Han comparison, or a SNP with a delta value > 0.8 in the French-Han comparison. We found that 31 of these regions also produced a top iHS, CLR, or XP-EHH score for at least one continent. As iHS and XP-EHH are based on haplotype frequencies, scores for these two tests and delta values are not expected to be totally independent of one another (although the overall correlation between delta values and test scores seems to be fairly low; for example, the Pearson correlation between Yoruba-Han delta values and raw XP-EHH scores in East Asia is only 0.1764). However, the presence of a high Fst SNP in a genomic region producing a high XP-EHH score has previously been taken as evidence that the region is a true target of selection rather than a false positive . It is also interesting to note that these 31 regions were not a random sample of the 61 high-delta regions. There were 4 clusters along the X chromosome - 18.8 to 20.8 Mb, 65 to 67.4 Mb, 72.2 to 74.2 Mb, and 108.6 to 110.6 Mb - of 4 or more consecutive high-delta regions, and of the 23 individual 400-kb regions in these clusters, 20 produced top iHS, XP-EHH, or CLR scores. Conversely, of the 19 high-delta regions that occurred in isolation (that is, they were not bordered on either side by another high-delta region), only 3 produced a top iHS, CLR, or XP-EHH score. It seems then that X-linked high-delta SNPs, particularly those that occur in clusters along the chromosome, tend to be found in chromosomal regions where iHS, CLR, and XP-EHH suggest that the haplotype structure is consistent with selection at that site.
Chromosome position of X-linked genes and regions found to be under selection in previous studies
XPEHH results 
Chromosomal regions of interest
In evaluating our results, we identified two regions that were clear outliers from the rest of the chromosome. The genic and SNP content of these regions are discussed in detail below along with the evidence that led us to identify them as outliers.
65 to 67 Mb
108.6 to 112.2 Mb
This area of the X chromosome was a clear outlier in the tests of selection. High iHS, CLR, and XP-EHH scores were observed between 108.6 and 112.2 Mb for all non-African continental groups. The highest scores were generally observed in the 800-kb region from 110.2 to 111 Mb. This area also contained a total of 13 high-delta SNPs from the Yoruba-Han comparison and 9 high-delta SNPs from the Yoruba-French comparison. As with the 65 to 67 Mb region, there is near total loss of haplotype heterozygosity in East Asia in this region (Figure 6). In examining this region of the X chromosome for genic targets of selection, we focused our attention from 110.2 to 111 Mb because of the distribution of iHS, CLR, and XP-EHH scores and the location of the aforementioned high-delta SNPs. It was not clear which of the five genes in this region is the most likely target of a selective sweep. Of these five genes, three - PAK3, DCX, and TRPC5 - encode proteins that are thought to be most active in the brain, with PAK3 and DCX being particularly involved in neuronal migration [31, 32]. A fourth gene, CAPN6, encodes a calcium-dependent cysteine protease also found in the brain and in the placenta , while the fifth gene, ALG13, has a yeast homolog active in N-glycosylation . PAK3, TRPC5, and CAPN6 have all been implicated in certain human diseases, including Alzheimer's disease for PAK3  and neurodegenerative disease for CAPN6 . Several cases of X-linked mental retardation have been linked to rare variants in PAK3  and recent research has theorized that TRPC5 may play a role in the pathogenesis of rheumatoid arthritis . All five of these genes are known to carry at least one non-synonymous mutation, although none of them have large intercontinental allele frequency differences.
62.2 to 63 Mb
High iHS, CLR, and XP-EHH scores tended to cluster on different parts of the chromosome for African and non-African populations. While the chromosomal segments described above produced high scores for the tests of selection in non-African groups, high CLR scores were observed over the interval 62.2 to 63 Mb for the two African groups. Specifically, the first and third highest CLR scores for the African hunter-gatherers occurred here along with the first and second highest CLR scores for the African agriculturists. This chromosomal region contains three genes - SPIN4, LOC92249, and ARHGEF9. Mutations in ARHGEF9, which encodes a Rho-like GTPase, are associated with epilepsy and hyperekplexia (hypersensitivity to certain external stimuli) . Little is known about SPIN4 and LOC92249. However, all three genes lie between 62.6 and 63 Mb while the highest CLR scores are observed between 62.2 and 62.6 Mb, so the target of selection in this region, if any, may lie outside of a known gene.
91.4 to 92.2 Mb
Another chromosomal region producing high test-of-selection scores in the African populations is 91.4 to 92.2 Mb, where the top two XP-EHH scores in both the African hunter-gatherers and agriculturists were observed. The highest XP-EHH scores in this region correspond to the SNPs found between 91.4 and 91.8 Mb, which is the location of the gene PCH11X, a member of the protocadherin family of cell adhesion and recognition proteins . PCH11X has a homolog on the Y chromosome and is not subject to X inactivation. Despite this, PCH11 transcript levels are twice as high in females compared to males . Previous studies have reported evidence of selection on particular members of the protocadherin family, including the alpha protocadherin cluster on chromosome 5 and recently PCH11Y [42, 43].
We have explored the possible impacts of both demography and selection on X-linked genetic variation. With regards to the former, we were particularly interested in investigating the possibility of male versus female demographic differences as these can be detected by comparing autosomal and X-linked data. Previous studies have found evidence for skewed gender ratios. Indeed, here we showed that evidence for asymmetries in both directions (male Ne/female Ne less than or greater than 1) can be found within a single dataset. Our results suggest that the picture of male versus female demography is complex and that each study addressing this question should be viewed as providing insight on a particular geographical scale and period in history rather than an absolute answer.
Of the three analyses that were potentially informative with respect to asymmetries in the demographics of the two genders (population structure using frappe, AMOVA, and delta analysis), we focused particularly on the results of the delta analysis. We did so because the differences between the X chromosome and the autosomes were so marked for this analysis, because these differences were robust to correction for drift, and because this feature of X chromosomal genetic variation has not previously been noted. We observed that more high-delta SNPs occurred in genes than would be expected by chance and that many high-delta SNPs occurred in regions with top iHS, CLR, or XP-EHH scores. Given these two pieces of evidence, we believe that while demographic processes and drift are important in shaping X-linked genotypic variation, the forces of selection are necessary to explain the observed excess of X-linked high-delta SNPs.
As selection is likely to have been important in shaping patterns of genetic variation on the X chromosome, we used iHS, CLR, and XP-EHH scores to identify possible targets of selection. Our objective in this was both to identify novel targets and use the diverse populations in our dataset to better define the geographical extent of previously described selective sweeps. We found that putative sweeps often encompass neighboring continents, but that the pattern is complex. Coop et al.  enumerated three major geographical distributions for selective sweeps as 'West Eurasian', 'East Asian', and 'non-African' sweeps, but we found evidence that certain subtypes exist. For instance, some non-African sweeps extend to Oceania and America, while some do not. We also found evidence for selection at several loci previously implicated as X-linked selection targets and our results show that previously described sweeps often extend outside the populations in which they were originally discovered. These findings reinforce the importance of using geographically diverse sample sets in scans for genomic targets of selection.
Finally, we highlighted two X-chromosomal regions that are outliers relative to the rest of the X chromosome with respect to SNP allele frequency distribution and haplotype structure. We believe that it is likely these loci were influenced by selection in the past. In the case of the 65 to 67 Mb region, we found a promising candidate for a target polymorphism - rs1385699, a non-synonymous SNP with known phenotypic associations and large allele frequency differences between African and East Asian populations. Overall, both regions represent interesting foci for future research into the role of selection in shaping genetic diversity on the X chromosome.
Materials and methods
We used the program frappe  to estimate the population structure underlying 16,297 X-linked SNP genotypes. The input files for frappe were generated using plink ; each X chromosome was converted into a diploid individual by making all loci homozygous for each haploid genotype. Frappe was then run with a maximum iteration of 500 and a step of 100 with K set to 7. The program output was displayed as a figure using Distruct . This process was repeated to estimate population structure for 19,632 chromosome 16 SNP genotypes.
The AMOVA analysis was carried out on the X chromosome using the program Arlequin . A total of 14 CEPH-HGDP population groupings were analyzed, including 12 that were previously examined by Rosenberg et al.  and Ramachandran et al.  using microsatellite markers. We also included two additional groupings by dividing the six African populations into hunter-gatherer and agriculturist groups. The AMOVA values reported for each of the 14 groupings were calculated using all of the X-linked markers that were polymorphic within a particular group. The 95% confidence intervals were calculated from 20,000 bootstrap runs. This process was then repeated to calculate the reported AMOVA values for chromosome 16.
We calculated the allele frequency difference, or delta, for each of the 656,995 SNPs in our dataset for three population pairs: Yoruba-Han, Yoruba-French, and Han-French. For each comparison, we selected all SNPs for which delta was greater than 0.9 and called these high-delta SNPs. Once we observed that there were no X-linked high-delta SNPs for the Han-French comparison, we enumerated all SNPs in this comparison for which delta exceeded 0.8. To determine how many of the X-linked SNPs in our dataset were in genic regions, we downloaded the chromosomal positions of known genes from the UCSC Genome Browser Website . All SNPs found within annotated gene boundaries were scored as genic SNPs. The ancestral allele for some SNPs was established using genotypes for two chimpanzees that were genotyped along with the CEPH-HGDP samples on the 650K Illumina chip. For SNPs that were fixed in the two chimpanzees, the fixed allele was taken as the ancestral allele. SNPs that were either polymorphic in the chimpanzees or for which there were missing data were not assigned an ancestral allele. We then searched for SNPs without an assigned ancestral allele in the NCBI database. Ancestral allele information from this database allowed us to assign ancestral alleles to some of these remaining SNPs.
Of the 16,297 X-chromosomal SNPs in our database, we were able to calculate raw iHSs for 11,623 to 15,532, depending on the continental group analyzed. We used an EHH cutoff value of 0.1, rather than the standard value of 0.05, in order to slightly increase the number of scores that we were able to obtain. For each continent, we then calculated the average raw iHS observed for each observed derived allele frequency. Any SNP with an iHS that differed by 2 or more from the average score for the same observed allele frequency was considered a high iHS SNP. After breaking the X chromosome up into 372 400-kb regions, we tabulated both the total number of SNPs with an iHS per region and the total number of high iHS SNPs per region. The iHS assigned to each 400-kb region is the ratio of these two values (number of high iHS SNPs: number of total SNPs with iHSs; Additional file 10).
For each continental group, we ran the short and long arms of the X chromosome separately, using a grid size of 30,000 for the short arm and 50,000 for the long arm. All SNPs that had been assigned an ancestral allele were treated as unfolded. For each sample set, we then converted the raw CLR scores into 372 data points by assigning to each 400-kb region the average CLR score observed in that region (Additional file 10).
For each continent and each test, a chromosomal region was assigned the value of the average XP-EHH score observed within that region for that test. As with iHS, XP-EHH scores cannot be calculated for SNPs near the centromere and the chromosome ends. This left some regions near these physical boundaries with no raw XP-EHH scores for some rounds of XP-EHH testing. These regions were assigned a value of zero for that round (Additional file 10).
Centre D'etude du Polymorphism Humaine-Human Genome Diversity Project
combined likelihood ratio
ectodysplasin 1A receptor
integrated haplotype score
single nucleotide polymorphism
transformed autosomal/expected X chromosome
cross population extended haplotype homozogysity.
This research was supported by NIH grant GM28016 to MWF. We would like to thank the members of the Pritchard lab at the University of Chicago who phased the data and provided us with the script used to calculate XP-EHH scores. We would also like to thank Jenna VanLiere who provided the script used to calculate iHSs and Melissa Hubisz who provided the CLR script.
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