Haplotypes histories as pathways of recombinations

MOTIVATION: The diversity of a haplotype, represented as a string of polymorphic sites along a DNA sequence, increases exponentially with the number of sites if recombinations are taking place. Reconstructing the history of recombinations compared with that of the polymorphic sites is thus extremely difficult. However, in the human genome, because of the relatively simple pattern of haplotype diversity dominated by a few ancestral haplotypes, the complexity of the recombinational network can be reduced, thus making its reconstruction feasible. We focus on the problem of inferring the recombination pathways starting with putative ancestral haplotypes and leading to new rare recombinant haplotypes. RESULTS: We describe classes of recombinations that represent the whole set of minimal recombination pathways leading to a new haplotype. We present an O(n(2)) algorithm that outputs such representative recombination pathways. We apply it to haplotypes of the 8 kb dystrophin gene segment dys44. AVAILABILITY: A software implementing the algorithm and some other extentions has been developed on a Java platform (JDK 1.3.1). It is freely available at http://www.iro.umontreal.ca/~mabrouk/     

Minimal sharing of Y-chromosome STR haplotypes among five endogamous population groups from western and southwestern India

We attempt to address the issue of genetic variation and the pattern of male gene flow among and between five Indian population groups of two different geographic and linguistic affiliations using Y-chromosome markers. We studied 221 males at three Y-chromosome biallelic loci and 184 males for the five Y-chromosome STRs. We observed 111 Y-chromosome STR haplotypes. An analysis of molecular variance (AMOVA) based on Y-chromosome STRs showed that the variation observed between the population groups belonging to two major regions (western and southwestern India) was 0.17%, which was significantly lower than the level of genetic variance among the five populations (0.59%) considered as a single group. Combined haplotype analysis of the five STRs and the biallelic locus 92R7 revealed minimal sharing of haplotypes among these five ethnic groups, irrespective of the similar origin of the linguistic and geographic affiliations; this minimal sharing indicates restricted male gene flow. As a consequence, most of the haplotypes were population specific. Network analysis showed that the haplotypes, which were shared between the populations, seem to have originated from different mutational pathways at different loci. Biallelic markers showed that all five ethnic groups have a similar ancestral origin despite their geographic and linguistic diversity.     

Haplotypes That Are Mosaic for Wild-Type and T Complex-Specific Alleles in Wild Mice

Two outstanding problems pertaining to the population dynamics and evolution of the t complex in mice concern the frequency of t haplotypes in the wild and the degree to which these haplotypes recombine with their wild-type homologs. To address these problems, the frequency and distribution of several t complex-associated restriction fragment variants in wild mice were estimated. Sixty-four versions of chromosome 17 from wild-derived Mus musculus musculus and Mus musculus domesticus were examined with DNA probes for six loci within the t complex that exhibit restriction fragment variation. All six probes detect variants that have heretofore been found exclusively associated with the t complex. Haplotype analysis of wild-derived chromosomes revealed a high frequency (45.3%) of "mosaic" haplotypes with a mixture of t-specific and wild-type variants and only one haplotype with t-specific variants at all six loci. When 12 well-characterized t haplotypes isolated from diverse geographic regions were analyzed, only three had a complete set of t-specific restriction fragments for the six loci examined. The preponderance of mosaic haplotypes in both groups of mice can be explained by any one of the following hypotheses: genetic recombination between t haplotypes and their wild-type homologs, the persistence in wild populations of haplotypes that have descended from ancestral partial t haplotypes, or that the restriction fragment variants fixed in the ancestral t haplotype were also fixed in some wild-type haplotypes. There is evidence to support all three of these hypotheses in our data. The allelic composition of some mosaic haplotypes indicates that they may have been formed by segmental recombination, either double crossing over or gene conversion, rather than by simple single crossovers. The occurrence of indistinguishable mosaic haplotypes in both M. m. musculus and M. m. domesticus suggests that these haplotypes are ancestral rather than recently derived.     

Lactase haplotype diversity in the Old World

Lactase persistence, the genetic trait in which intestinal lactase activity persists at childhood levels into adulthood, varies in frequency in different human populations, being most frequent in northern Europeans and certain African and Arabian nomadic tribes, who have a history of drinking fresh milk. Selection is likely to have played an important role in establishing these different frequencies since the development of agricultural pastoralism approximately 9,000 years ago. We have previously shown that the element responsible for the lactase persistence/nonpersistence polymorphism in humans is cis-acting to the lactase gene and that lactase persistence is associated, in Europeans, with the most common 70-kb lactase haplotype, A. We report here a study of the 11-site haplotype in 1,338 chromosomes from 11 populations that differ in lactase persistence frequency. Our data show that haplotype diversity was generated both by point mutations and recombinations. The four globally common haplotypes (A, B, C, and U) are not closely related and have different distributions; the A haplotype is at high frequencies only in northern Europeans, where lactase persistence is common; and the U haplotype is virtually absent from Indo-European populations. Much more diversity is seen in sub-Saharan Africans than in non-Africans, consistent with an "Out of Africa" model for peopling of the Old World. Analysis of recent recombinant haplotypes by allele-specific PCR, along with deduction of the root haplotype from chimpanzee sequence, allowed construction of a haplotype network that assisted in evaluation of the relative roles of drift and selection in establishing the haplotype frequencies in the different populations. We suggest that genetic drift was important in shaping the general pattern of non-African haplotype diversity, with recent directional selection in northern Europeans for the haplotype associated with lactase persistence.     

Phylogeny of human beta-globin haplotypes and its implications for recent human evolution

The evolutionary histories and relationships among African, Eurasian, and Pacific Island populations are investigated by using observations on five polymorphic restriction sites in the beta-globin gene cluster. We present new data on 222 chromosomes from a global sample and combine these with previously published observations on 591 chromosomes. It is shown that the data are rich in rare haplotypes and that rare variants are not helpful for standard methods of population structure analysis. Consequently, a new approach is developed. We first consider the phylogeny of beta-globin haplotypes. The roles of mutation, gene conversion, and recombination in the generation of haplotype diversity are specifically focused upon. The relationships among human populations are then inferred from the phylogenetic relationships among the haplotypes, their presence or absence, and frequencies within populations. Questions regarding whether or not a phyletic process can account for relationships among the major geographical populations and whether or not an extant human population exhibits the qualities that would be expected of an ancestral group are addressed. The results of this analysis support an African origin for modern Homo sapiens and a phyletic structuring of the major geographical regions. However, it is shown that divergence times for the various populations cannot be determined from these data.     

Combined use of biallelic and microsatellite Y-chromosome polymorphisms to infer affinities among African populations.

To define Y-chromosome haplotypes, we studied seven biallelic polymorphic sites. We combined data with those from four dinucleotide-repeat polymorphisms, to establish Y-chromosome compound superhaplotypes. Eight biallelic haplotypes that matched the dendrogram proposed by other investigators were identified in 762 Y chromosomes from 25 African populations. For each biallelic site, coalescence time of lineages carrying the derived allele was estimated and compared with previous estimates. The "ancestral" haplotype (haplotype 1A) was observed among Ethiopians, "Khoisan" (!Kung and Khwe), and populations from northern Cameroon. Microsatellite distributions within this haplotype showed that the Khoisan haplotypes 1A are widely divergent from those of the other two groups. Populations from northern Africa and northern Cameroon share a haplotype (i.e., 1C), which is not observed in other African populations but represents a major Eurasian cluster. Haplotypes 1C of northern Cameroon are clearly distinct from those of Europe, whereas haplotypes 1C of northern African are well intermingled with those of the other two groups. Apportionment of diversity for the Y-chromosomal biallelic haplotypes was calculated after populations were clustered into different configurations. Despite some correspondence between language affiliation and genetic similarity, geographic proximity seems to be a better predictor of genetic affinity.     

Genetic variation and population structure of the Japanese sika deer (Cervus nippon) in the Tohoku District based on mitochondrial D-loop sequences

The sika deer (Cervus nippon) once inhabited the entire Tohoku District, the northeastern part of the main island of Japan. Currently, they are isolated as three discontinuous populations on Mt. Goyo, the Oshika Peninsula, and Kinkazan Island. To assess the genetic diversity and relationships among the sika deer populations in the Tohoku District, we analyzed the mitochondrial DNA D-loop sequences from 177 individuals. We detected a total of five haplotypes. Three haplotypes were present in the population from Mt. Goyo at a haplotype diversity of 0.235 ± 0.061, two haplotypes in the population from the Oshika Peninsula at 0.171 ± 0.064, and only one haplotype was detected in the population from the Kinkazan Island. A significant genetic differentiation was observed among all population pairs. Collectively, our data supports the observed population bottlenecks in the past. Four of the five haplotypes were specific to one of the three populations, whereas only one haplotype was shared between the Mt. Goyo and the Oshika Peninsula populations. This common haplotype may indicate a common ancestral population in the Tohoku District. Conversely, the D-loop haplotypes were completely different among the Kinkazan Island and Oshika Peninsula populations. The lack of a shared haplotype indicates that female gene flow between the two populations is very limited and that the 0.6 km strait acts as a strong barrier.     

Contribution of mutation, recombination, and gene conversion to chicken MHC-B haplotype diversity

The Mhc is a highly conserved gene region especially interesting to geneticists because of the rapid evolution of gene families found within it. High levels of Mhc genetic diversity often exist within populations. The chicken Mhc is the focus of considerable interest because of the strong, reproducible infectious disease associations found with particular Mhc-B haplotypes. Sequence data for Mhc-B haplotypes have been lacking thereby hampering efforts to systematically resolve which genes within the Mhc-B region contribute to well-defined Mhc-B-associated disease responses. To better understand the genetic factors that generate and maintain genomic diversity in the Mhc-B region, we determined the complete genomic sequence for 14 Mhc-B haplotypes across a region of 59 kb that encompasses 14 gene loci ranging from BG1 to BF2. We compared the sequences using alignment, phylogenetic, and genome profiling methods. We identified gene structural changes, synonymous and non-synonymous polymorphisms, insertions and deletions, and allelic gene rearrangements or exchanges that contribute to haplotype diversity. Mhc-B haplotype diversity appears to be generated by a number of mutational events. We found evidence that some Mhc-B haplotypes are derived by whole- and partial-allelic gene conversion and homologous reciprocal recombination, in addition to nucleotide mutations. These data provide a framework for further analyses of disease associations found among these 14 haplotypes and additional haplotypes segregating and evolving in wild and domesticated populations of chickens.     

Chlamydomonas Genome Resource for Laboratory Strains Reveals a Mosaic of Sequence Variation,Identifies True Strain Histories,and Enables Strain-Specific Studies

Chlamydomonas reinhardtii is a widely used reference organism in studies of photosynthesis, cilia, and biofuels. Most research in this field uses a few dozen standard laboratory strains that are reported to share a common ancestry, but exhibit substantial phenotypic differences. In order to facilitate ongoing Chlamydomonas research and explain the phenotypic variation, we mapped the genetic diversity within these strains using whole-genome resequencing. We identified 524,640 single nucleotide variants and 4812 structural variants among 39 commonly used laboratory strains. Nearly all (98.2%) of the total observed genetic diversity was attributable to the presence of two, previously unrecognized, alternate haplotypes that are distributed in a mosaic pattern among the extant laboratory strains. We propose that these two haplotypes are the remnants of an ancestral cross between two strains with ∼2% relative divergence. These haplotype patterns create a fingerprint for each strain that facilitates the positive identification of that strain and reveals its relatedness to other strains. The presence of these alternate haplotype regions affects phenotype scoring and gene expression measurements. Here, we present a rich set of genetic differences as a community resource to allow researchers to more accurately conduct and interpret their experiments with Chlamydomonas.     

Microsatellite haplotypes of the Y-chromosome demonstrate the absence of subdivisions and presence of several components in the Tuvinian male gene pool

The haplotype analysis of seven Y-chromosome microsatellites in three regional populations of Tuvinians revealed high intrapopulation variation in the male gene pool of the modern population of the Tuva Republic. In total, 49 haplotypes were found in 111 individuals; only four haplotypes occurred at a frequency higher than 5%. High genetic diversity (H = 0.935) suggested a high power of discrimination for the Y-chromosome haplotypes. The analysis of molecular variance (AMOVA) and other data did not reveal subdivision of the Tuvinian population with respect to Y-chromosome haplotypes. Most haplotypes found in Tuvinians formed two lines. Line A included approximately 64% of the haplotypes found, line B, approximately 24%. A putative ancestral haplotype of line B was similar to a haplotype most common in modern Caucasoids (Md = 3), whereas a putative ancestral haplotype of line A proved to be distant from the ancestral haplotype of line A and haplotypes common for Caucasoids and Mongoloids. Estimates of the age of the Y-chromosome lines showed that the male gene pool of modern Tuvinians originated in the late Paleolithic or Neolithic period. With two methods, the age of line A was estimated at 3500 or 18,000 years and the age of line B was approximately at 5500 or 15,000 years. Considering the less conservative estimates to be more reliable, line B was assumed to originate from the ancient Caucasoid population of the Tuva region. The more widespread and evolutionarily younger line A was associated with the peopling region by ancient Mongoloid tribes of the Turkic language group in the Hun-Sarmatian period.     

Corticotropin releasing hormone (CRH) gene variation: comprehensive resequencing for variant and molecular haplotype discovery in monosomic hybrid cell lines.

Candidate gene association studies have met with mixed success due to many reasons including incomplete surveys of genetic variation and differences in patterns of genetic variation among study populations. We present the results of comprehensive variant discovery for the corticotropin releasing hormone gene (CRH on chromosome 8) encoding a neuropeptide that is central to many physiologic pathways. Mouse-human hybrid cell lines were constructed that are monosomic for human chromosome 8 for resequencing of separated CRH alleles to identify variants and directly determine their chromosomal phase for three major ethnic groups including African Americans (AA), Mexican Americans (MA) and European Americans (EA). We also resequenced diploid individuals to evaluate single nucleotide polymorphism (SNP) discovery in the limited numbers of monosomic hybrid cell lines. Our results show that CRH variation is very different in AA, yielding larger numbers of variants and haplotypes compared to MA and EA. Analysis of LD structure found three haplotype blocks in AA and two blocks in EA. Comparisons between AA and EA groups yielded extremely high measures of genetic differentiation (Wright's F(ST)>0.6), likely reflecting disruptive selection in CRH evolution. Network analysis showed that AA have retained an ancestral CRH haplotype, while the most common EA haplotype is derived from a single recombination event.     

Power of neutrality tests to detect bottlenecks and hitchhiking

The power of several neutrality tests to reject a simple bottleneck model is examined in a coalescent framework. Several tests are considered including some relying on the frequency spectrum of mutations and some reflecting the linkage disequilibrium structure of the data. We evaluate the effect of the age and of the strength of the bottleneck, and their interaction. We contrast two qualitatively different bottleneck effects depending on their strength. In genealogical terms, during severe bottlenecks, all lineages coalesce leading to a star-like gene genealogy of the sample. Some time after the bottleneck, once new mutations have arisen, they tend to show an excess of rare variants and a slight excess of haplotypes. On the contrary, more moderate bottlenecks allow several lineages to survive the demographic crash, leading to a balanced genealogy with long internal branches. Soon after the event, data tend to show an excess of intermediate frequency variants and a deficit of haplotypes. We show that for moderate sequencing efforts, severe bottlenecks can be detected only after an intermediate time period has allowed for mutations to occur, preferably by frequency spectrum statistics. Moderate bottlenecks can be more easily detected for more recent events, especially using haplotype statistics. Finally, for a single locus, the bottleneck results closely approximate those of a simple hitchhiking model. The main difference concerns the frequency distribution of mutations and haplotypes after moderate perturbations. Hitchhiking increases the number of rare ancestral mutations and leads to a more predominant major haplotype class. Thus, despite a number of common features between the two processes, hitchhiking cannot be strictly modeled by bottlenecks.     

High diversity of alpha-globin haplotypes in a Senegalese population, including many previously unreported variants.

RFLP haplotypes at the alpha-globin gene complex have been examined in 190 individuals from the Niokolo Mandenka population of Senegal: haplotypes were assigned unambiguously for 210 chromosomes. The Mandenka share with other African populations a sample size-independent haplotype diversity that is much greater than that in any non-African population: the number of haplotypes observed in the Mandenka is typically twice that seen in the non-African populations sampled to date. Of these haplotypes, 17.3% had not been observed in any previous surveys, and a further 19.1% have previously been reported only in African populations. The haplotype distribution shows clear differences between African and non-African peoples, but this is on the basis of population-specific haplotypes combined with haplotypes common to all. The relationship of the newly reported haplotypes to those previously recorded suggests that several mutation processes, particularly recombination as homologous exchange or gene conversion, have been involved in their production. A computer program based on the expectation-maximization (EM) algorithm was used to obtain maximum-likelihood estimates of haplotype frequencies for the entire data set: good concordance between the unambiguous and EM-derived sets was seen for the overall haplotype frequencies. Some of the low-frequency haplotypes reported by the estimation algorithm differ greatly, in structure, from those haplotypes known to be present in human populations, and they may not represent haplotypes actually present in the sample.     

Haplotype variation in the ACE gene in global populations, with special reference to India, and an alternative model of evolution of haplotypes

Angiotensin-I-converting enzyme (ACE) is known to be associated with human cardiovascular and psychiatric pathophysiology. We have undertaken a global survey of the haplotypes in ACE gene to study diversity and to draw inferences on the nature of selective forces that may be operating on this gene. We have investigated the haplotype profiles reconstructed using polymorphisms in the regulatory (rs4277405, rs4459609, rs1800764, rs4292, rs4291), exonic (rs4309, rs4331, rs4343), and intronic (rs4340; Alu [I/D]) regions covering 17.8 kb of the ACE gene. We genotyped these polymorphisms in a large number of individuals drawn from 15 Indian ethnic groups and estimated haplotype frequencies. We compared the Indian data with available data from other global populations. Globally, five major haplotypes were observed. High-frequency haplotypes comprising mismatching alleles at the loci considered were seen in all populations. The three most frequent haplotypes among Africans were distinct from the major haplotypes of other world populations. We have studied the evolution of the two major haplotypes (TATATTGIA and CCCTCCADG), one of which contains an Alu insertion (I) and the other a deletion (D), seen most frequently among Caucasians (68%), non-African HapMap populations (65?C88%), and Indian populations (70?C95%) in detail. The two major haplotypes among Caucasians are reported to represent two distinct clades A and B. Earlier studies have postulated that a third clade C (represented by the haplotypes TACATCADG and TACATCADA) arose from an ancestral recombination event between A and B. We find that a more parsimonious explanation is that clades A and B have arisen by recombination between haplotypes belonging to clade C and a high-frequency African haplotype CCCTTCGIA. The haplotypes, which according to our hypothesis are the putative non-recombinants (PuNR), are uncommon in all non-African populations (frequency range 0?C12%). Conversely, the frequencies of the putative recombinant haplotypes (PuR) are very low in the Africans populations (2?C8%), indicating that the recombination event is likely to be ancient and arose before, perhaps shortly prior to, the global dispersal of modern humans. The global frequency spectrum of the PuR and the PuNR is difficult to explain only by drift. It appears likely that the ACE gene has been undergoing a combination of different selective pressures.     

Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex

Human populations are endowed with a sophisticated genetic diversity of complement C4 and its flanking genes RP, CYP21, and TNX in the RCCX modules of the major histocompatibility complex class III region. We applied definitive techniques to elucidate (a) the complement C4 polymorphisms in gene sizes, gene numbers, and protein isotypes and (b) their gene orders. Several intriguing features are unraveled, including (1) a trimodular RCCX haplotype with three long C4 genes expressing C4A protein only, (2) two trimodular haplotypes with two long (L) and one short (S) C4 genes organized in LSL configurations, (3) a quadrimodular haplotype with four C4 genes organized in a SLSL configuration, and (4) another quadrimodular structure, with four long C4 genes (LLLL), that has the human leukocyte antigen haplotype that is identical to ancestral haplotype 7.2 in the Japanese population. Long-range PCR and PshAI-RFLP analyses conclusively revealed that the short genes from the LSL and SLSL haplotypes are C4A. In four informative families, an astonishingly complex pattern of genetic diversity for RCCX haplotypes with one, two, three and four C4 genes is demonstrated; each C4 gene may be long or short, encoding a C4A or C4B protein. Such diversity may be related to different intrinsic strengths among humans to defend against infections and susceptibilities to autoimmune diseases.     

基于核基因和叶绿体基因的台湾水韭遗传多样性和遗传结构的分析

利用核基因和叶绿体基因对台湾水韭（Isoetes taiwanensis Devol）2个居群20个样本的遗传多样性和遗传结构进行了分析,并对台湾水韭的保育提出了建议。核基因的检测结果显示,2个居群共存在18个单倍型,单倍型多样性为0.9842,核苷酸多样性为0.00215,居群间基因流N_m为4.26,居群间分化系数G_st值为0.05543;叶绿体DNA的检测结果显示,单倍型数目为6,单倍型多样性为0.6211,核苷酸多样性为0.00326。其中台北居群的单倍型多样性和核苷酸多样性均比金门居群高。核基因和叶绿体基因的AMOVA分析显示,居群内的遗传差异远高于居群间。台湾水韭的核苷酸多样性相对其他水韭属植物较低,可能与台湾水韭的染色体倍型以及狭域分布有关。居群结构的形成可能和基因流以及奠基者效应有关。宜采用原地和迁地保护的方法对居群进行保护。     

Detecting and Characterizing Genomic Signatures of Positive Selection in Global Populations

Natural selection is a significant force that shapes the architecture of the human genome and introduces diversity across global populations. The question of whether advantageous mutations have arisen in the human genome as a result of single or multiple mutation events remains unanswered except for the fact that there exist a handful of genes such as those that confer lactase persistence, affect skin pigmentation, or cause sickle cell anemia. We have developed a long-range-haplotype method for identifying genomic signatures of positive selection to complement existing methods, such as the integrated haplotype score (iHS) or cross-population extended haplotype homozygosity (XP-EHH), for locating signals across the entire allele frequency spectrum. Our method also locates the founder haplotypes that carry the advantageous variants and infers their corresponding population frequencies. This presents an opportunity to systematically interrogate the whole human genome whether a selection signal shared across different populations is the consequence of a single mutation process followed subsequently by gene flow between populations or of convergent evolution due to the occurrence of multiple independent mutation events either at the same variant or within the same gene. The application of our method to data from 14 populations across the world revealed that positive-selection events tend to cluster in populations of the same ancestry. Comparing the founder haplotypes for events that are present across different populations revealed that convergent evolution is a rare occurrence and that the majority of shared signals stem from the same evolutionary event.     

Arms races with mitochondrial genome soft sweeps in a gynodioecious plant,Plantago lanceolata

Biological situations involving conflict can create arms race situations with repeated fixations of different functional variants, producing selective sweeps and lowering neutral diversity in genome regions linked to the functional locus. However, they can sometimes lead to balancing selection, potentially creating long coalescent times for sites with functionally different variants, and, if recombination occurs rarely, for extended haplotypes carrying such variants. We tested between these possibilities in a gynodioecious plant, Plantago lanceolata, in which cytoplasmic male‐sterility factors conflict with nuclear restorers of male fertility. We find low mitochondrial diversity, which does not support very long‐term coexistence of highly diverged mitochondrial haplotypes. Interestingly, however, we found a derived haplotype that is associated with male fertility in a restricted geographic region, and that has fixed differences from the ancestral sequence in several genes, suggesting that it did not arise very recently. Taken together, the results suggest arms race events that involved “soft" selective sweeps involving a moderately old‐established haplotype, consistent with the frequency fluctuations predicted by theoretical models of gynodioecy.     

Worldwide genetic analysis of the CFTR region

Mutations at the cystic fibrosis transmembrane conductance regulator gene (CFTR) cause cystic fibrosis, the most prevalent severe genetic disorder in individuals of European descent. We have analyzed normal allele and haplotype variation at four short tandem repeat polymorphisms (STRPs) and two single-nucleotide polymorphisms (SNPs) in CFTR in 18 worldwide population samples, comprising a total of 1,944 chromosomes. The rooted phylogeny of the SNP haplotypes was established by typing ape samples. STRP variation within SNP haplotype backgrounds was highest in most ancestral haplotypes-although, when STRP allele sizes were taken into account, differences among haplotypes became smaller. Haplotype background determines STRP diversity to a greater extent than populations do, which indicates that haplotype backgrounds are older than populations. Heterogeneity among STRPs can be understood as the outcome of differences in mutation rate and pattern. STRP sites had higher heterozygosities in Africans, although, when whole haplotypes were considered, no significant differences remained. Linkage disequilibrium (LD) shows a complex pattern not easily related to physical distance. The analysis of the fraction of possible different haplotypes not found may circumvent some of the methodological difficulties of LD measure. LD analysis showed a positive correlation with locus polymorphism, which could partly explain the unusual pattern of similar LD between Africans and non-Africans. The low values found in non-Africans may imply that the size of the modern human population that emerged "Out of Africa" may be larger than what previous LD studies suggested.