Larger genetic differences within africans than between Africans and Eurasians

The worldwide pattern of single nucleotide polymorphism (SNP) variation is of great interest to human geneticists, population geneticists, and evolutionists, but remains incompletely understood. We studied the pattern in noncoding regions, because they are less affected by natural selection than are coding regions. Thus, it can reflect better the history of human evolution and can serve as a baseline for understanding the maintenance of SNPs in human populations. We sequenced 50 noncoding DNA segments each approximately 500 bp long in 10 Africans, 10 Europeans, and 10 Asians. An analysis of the data suggests that the sampling scheme is adequate for our purpose. The average nucleotide diversity (pi) for the 50 segments is only 0.061% +/- 0.010% among Asians and 0.064% +/- 0.011% among Europeans but almost twice as high (0.115% +/- 0.016%) among Africans. The African diversity estimate is even higher than that between Africans and Eurasians (0.096% +/- 0.012%). From available data for noncoding autosomal regions (total length = 47,038 bp) and X-linked regions (47,421 bp), we estimated the pi-values for autosomal regions to be 0.105, 0.070, 0.069, and 0.097% for Africans, Asians, Europeans, and between Africans and Eurasians, and the corresponding values for X-linked regions to be 0.088, 0.042, 0.053, and 0.082%. Thus, Africans differ from one another slightly more than from Eurasians, and the genetic diversity in Eurasians is largely a subset of that in Africans, supporting the out of Africa model of human evolution. Clearly, one must specify the geographic origins of the individuals sampled when studying pi or SNP density.     

High polymorphism at the human melanocortin 1 receptor locus

Variation in human skin/hair pigmentation is due to varied amounts of eumelanin (brown/black melanins) and phaeomelanin (red/yellow melanins) produced by the melanocytes. The melanocortin 1 receptor (MC1R) is a regulator of eu- and phaeomelanin production in the melanocytes, and MC1R mutations causing coat color changes are known in many mammals. We have sequenced the MC1R gene in 121 individuals sampled from world populations with an emphasis on Asian populations. We found variation at five nonsynonymous sites (resulting in the variants Arg67Gln, Asp84Glu, Val92Met, Arg151Cys, and Arg163Gln), but at only one synonymous site (A942G). Interestingly, the human consensus protein sequence is observed in all 25 African individuals studied, but at lower frequencies in the other populations examined, especially in East and Southeast Asians. The Arg163Gln variant is absent in the Africans studied, almost absent in Europeans, and at a low frequency (7%) in Indians, but is at an exceptionally high frequency (70%) in East and Southeast Asians. The MC1R gene in common and pygmy chimpanzees, gorilla, orangutan, and baboon was sequenced to study the evolution of MC1R. The ancestral human MC1R sequence is identical to the human consensus protein sequence, while MC1R varies considerably among higher primates. A comparison of the rates of substitution in genes in the melanocortin receptor family indicates that MC1R has evolved the fastest. In addition, the nucleotide diversity at the MC1R locus is shown to be several times higher than the average nucleotide diversity in human populations, possibly due to diversifying selection.     

Global patterns of human DNA sequence variation in a 10-kb region on chromosome 1

Human DNA variation is currently a subject of intense research because of its importance for studying human origins, evolution, and demographic history and for association studies of complex diseases. A approximately 10-kb region on chromosome 1, which contains only four small exons (each <155 bp), was sequenced for 61 humans (20 Africans, 20 Asians, and 21 Europeans) and for 1 chimpanzee, 1 gorilla, and 1 orangutan. We found 52 polymorphic sites among the 122 human sequences and 382 variant sites among the human, chimpanzee, gorilla, and orangutan sequences. For the introns sequenced (8,991 bp), the nucleotide diversity (pi) was 0.058% among all sequences, 0.076% among the African sequences, 0.047% among the Asian sequences, and 0.045% among the European sequences. A compilation of data revealed that autosomal regions have, on average, the highest pi value (0.091%), X-linked regions have a somewhat lower pi value (0.079%), and Y-linked regions have a very low pi value (0.008%). The lower polymorphism in the present region may be due to a lower mutation rate and/or selection in the gene containing these introns or in genes linked to this region. The present region and two other 10-kb noncoding regions all show a strong excess of low-frequency variants, indicating a relatively recent population expansion. This region has a low mutation rate, which was estimated to be 0.74 x 10 per nucleotide per year. An average estimate of approximately 12,600 for the long-term effective population size was obtained using various methods; the estimate was not far from the commonly used value of 10,000. Fu and Li's tests rejected the assumption of an equilibrium neutral Wright-Fisher population, largely owing to the high proportion of low-frequency variants. The age of the most recent common ancestor of the sequences in our sample was estimated to be more than 1 Myr. Allowing for some unrealistic assumptions in the model, this estimate would still suggest an age of more than 500,000 years, providing further evidence for a genetic history of humans much more ancient than the emergence of modern humans. The fact that many unique variants exist in Europe and Asia also suggests a fairly long genetic history outside of Africa and argues against a complete replacement of all indigenous populations in Europe and Asia by a small Africa stock. Moreover, the ancient genetic history of humans indicates no severe bottleneck during the evolution of humans in the last half million years; otherwise, much of the ancient genetic history would have been lost during a severe bottleneck. We suggest that both the "Out of Africa" and the multiregional models are too simple to explain the evolution of modern humans.     

Genome-wide SNP typing reveals signatures of population history

Single-nucleotide polymorphism (SNP) arrays have become a popular technology for disease-association studies, but they also have potential for studying the genetic differentiation of human populations. Application of the Affymetrix GeneChip Human Mapping 500K Array Set to a population of 102 individuals representing the major ethnic groups in the United States (African, Asian, European, and Hispanic) revealed patterns of gene diversity and genetic distance that reflected population history. We analyzed allelic frequencies at 388,654 autosomal SNP sites that showed some variation in our study population and 10% or fewer missing values. Despite the small size (23-31 individuals) of each subpopulation, there were no fixed differences at any site between any two subpopulations. As expected from the African origin of modern humans, greater gene diversity was seen in Africans than in either Asians or Europeans, and the genetic distance between the Asian and the European populations was significantly lower than that between either of these two populations and Africans. Principal components analysis applied to a correlation matrix among individuals was able to separate completely the major continental groups of humans (Africans, Asians, and Europeans), while Hispanics overlapped all three of these groups. Genes containing two or more markers with extraordinarily high genetic distance between subpopulations were identified as candidate genes for health differences between subpopulations. The results show that, even with modest sample sizes, genome-wide SNP genotyping technologies have great promise for capturing signatures of gene frequency difference between human subpopulations, with applications in areas as diverse as forensics and the study of ethnic health disparities.     

Haptoglobin gene promoter polymorphism and haplotypes are unique in different populations

We investigated the distribution of haptoglobin (HP) alleles and haplotypes among Africans (Ghanaians), Europeans (from South Africa), and Chinese. HP*1F was present only in Africans and Europeans, whereas HP*del was unique to Chinese. Six base substitutions at the promoter region were population specific. Only 3 out of 18 haplotypes were shared among the populations. A probable application of HP in human population genetics appears legitimate.     

Climate and the evolution of skull metrics in man.

Two types of data, anthropometric and gene frequencies, may be used to reconstruct human evolution. Previous research, reconstructing the history of racial differentiation on the basis of gene frequencies, indicated that the major separation between human groups was that between Africans and Europeans on one side and peoples from Australia, East Asia and Americas on the other. A similar attempt by Howells ('73b), based on skull measurements in 17 ancient populations, in agreement with earlier anthropometric data, showed the major separation to be between Africans and Australians on one side and Europeans, Asians and Americans on the other. Climate could be a contributing factor to the observed differences in skull and anthropometric measurements. Howells' data showed high correlations with several climatic indicators. Carrying out the phylogenetic analysis after elimination by linear regression of the effects of climate has resolved to a great extent the discrepancy between anthropometric and gene frequency data.     

Association between Common Polymorphism near the MC4R Gene and Obesity Risk: A Systematic Review and Meta-Analysis

Background

Genome-wide association studies on Europeans have shown that two polymorphisms (rs17782313, rs12970134) near the melanocortin 4 receptor (MC4R) gene were associated with increased risk of obesity. Subsequently studies among different ethnic populations have shown mixed results with some confirming and others showing inconsistent results, especially among East Asians and Africans. We performed a comprehensive meta-analysis of various studies from different ethnic populations to assess the association of the MC4R polymorphism with obesity risk.

Methods

We retrieved all published literature that investigated association of MC4R variants with obesity from PubMed and Embase. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model.

Results

A total of 61 studies (80,957 cases/220,223 controls) for rs17782313 polymorphism (or proxy) were included in the meta-analysis. The results suggested that rs17782313 polymorphism was significantly associated with obesity risk (OR = 1.18, 95%CI = 1.15–1.21, p<0.001). Similar trends were observed among subgroups of Europeans and East Asians, adults and children, studies with high quality score, and for each five MC4R polymorphisms independently.

Conclusions

The present meta-analysis confirms the significant association of MC4R polymorphism with risk of obesity. Further studies should be conducted to identify the causal variant and the underlying mechanisms of the identified association.     

Beta-globin gene haplotype characteristics of Colombian Amerinds in South America

Haplotypes and subhaplotypes in the beta-globin gene cluster were identified in 146 and 156 chromosomes, respectively, of three tribes of Colombian Amerinds. Subhaplotype [+----] was a major one in Colombian Amerinds as in most human ethnic groups except Africans. A major subhaplotype [----+] in Africans was observed in only one chromosome. The framework 2 frequencies were very low (0.018-0.067). Haplotype [+----++], which is a major one in Europeans, but not in Asians, and [+-----+], which is a major one in Asians, but not in Europeans, were two major haplotypes. Subhaplotype data showed the closest genetic affinities between Colombian Amerinds and Polynesians, Micronesians, and Asians, but the haplotype data did not necessarily support this.     

Genetic relationships of Europeans, Asians and Africans and the origin of modern Homo sapiens

To study the evolutionary relationships of the three major groups of humans, Europeans, Asians and Africans, the genetic distances between them were computed by using 4 different sets of genetic loci (84 protein loci, 33 blood group loci, 8 HLA and immunoglobulin loci, and 61 DNA markers). The results obtained indicate that the overall genetic distance between Europeans and Asians is significantly lower than that between Europeans and Africans of that between Asians and Africans and support the hypothesis of an African origin of modern humans. This seems to be the first study to establish the evolutionary relationships of the three major groups of humans at a statistically significant level.     

Confirmation of the potential usefulness of two human beta globin pseudogene markers to estimate gene flows to and from sub-Saharan Africans

Two polymorphic sites, -107 and -100 with respect to the "cap" site of the human beta globin pseudogene, recently discovered in our laboratory, turned out to have an ethnically complementary distribution. The first site is polymorphic in Europeans, North Africans, Indians (Hindu), and Oriental Asians, and monomorphic in sub-Saharan Africans. Conversely, the second site is polymorphic in sub-Saharan African populations and monomorphic in the aforementioned populations. Here we report the gene frequencies of these two polymorphic sites in nine additional populations (Egyptians, Spaniards, Japanese, Chinese, Filipinos, Vietnamese, Africans from Togo and from Benin, and Pygmies), confirming their ethnospecificity and, through the analysis of these two markers in Oromo and Amhara of Ethiopia (two mixed populations), their usefulness in genetic admixture studies. Moreover, we studied another marker polymorphic in sub-Saharan African populations only, a TaqI restriction fragment length polymorphism located in the same region as the present markers, demonstrating the absence of linkage disequilibrium between it and the -100 site, so that we can exclude that the information they provide is redundant.     

Phylogenetic affiliation of ancient and contemporary humans inferred from mitochondrial DNA.

Nucleotide sequence analysis of the major non-coding region of human mitochondrial DNA (mtDNA) from three major races was extended with data from 27 contemporary Mongoloids (20 from southeast Asia, seven from America) and 11 Ancient Japanese bones (five from Jomon Age; 3000-6000 years BP, six from the early modern Ainu; 200-300 years BP). In both cases, the sequence was determined directly from the polymerase chain reaction products. Based on a comparison of the 482 base pair sequences from a total of 128 contemporary humans, the nucleotide diversity is estimated to be 1.46%, which is three times higher than the corresponding value estimated from restriction-enzyme analysis of the whole mtDNA genome. The phylogenetic tree revealed that all lineages are classified into at least five clusters designated as C1-C5. C1 consists exclusively of Africans, and most Asians and Europeans formed C2, C3, C5 and C4, respectively. Phylogenetic analysis also indicated that part of the Asians, including the Japanese, subsequently diverged from the majority of Africans, and that Asians can therefore be separated into two distinct groups. Native Americans, however, appeared only in C3 and C5, suggesting that the size of the founder population was not so large during the peopling of American. Nucleotide sequences derived from ancient bones in a highly polymorphic region were also compared with those of contemporary humans. The nucleotide diversity among the 139 sequences in the region was estimated to be 2.26%. A group of ancient Japanese, including both Jomon peoples and the Ainu, showed a close phylogenetic affiliation with one group of contemporary Japanese and southeast Asians.(ABSTRACT TRUNCATED AT 250 WORDS)     

Brief communication: Population data support the adaptive nature of HACNS1 sapiens/neandertal‐chimpanzee differences in a limb expression domain

The 546‐base pair enhancer of limb expression HACNS1, which is highly constrained in all terrestrial vertebrates, has accumulated 16 human‐specific changes after the human‐chimpanzee split. There has been discussion whether this process was driven by positive selection or biased gene conversion, without considering population data. We studied 83 South Amerindian, 11 Eskimo, 35 Europeans, 37 Bantu, and non‐Bantu Sub‐Saharan speakers, and 28 Brazilian mestizo samples and found no variation in this DNA region. Similar lack of variability in this region was found in four Africans, five Europeans or Euro‐derived, two Asians, one Paleo‐Eskimo, and one Neandertal sequence, whose whole genomes are publicly available. No difference was found. This result favors the interpretation of past positive and present conservative selection, as would expected in a region which influences Homo‐specific traits as important as opposable thumbs, manual dexterity, and bipedal walking. Am J Phys Anthropol, 2010. © 2010 Wiley‐Liss, Inc.     

Molecular evolution of a malaria resistance gene (DARC) in primates

Genes involved in host-pathogen interactions are often strongly affected by positive natural selection. The Duffy antigen, coded by the Duffy antigen receptor for chemokines (DARC) gene, serves as a receptor for Plasmodium vivax in humans and for Plasmodium knowlesi in some nonhuman primates. In the majority of sub-Saharan Africans, a nucleic acid variant in GATA-1 of the gene promoter is responsible for the nonexpression of the Duffy antigen on red blood cells and consequently resistance to invasion by P. vivax. The Duffy antigen also acts as a receptor for chemokines and is expressed in red blood cells and many other tissues of the body. Because of this dual role, we sequenced a ~3,000-bp region encompassing the entire DARC gene as well as part of its 5' and 3' flanking regions in a phylogenetic sample of primates and used statistical methods to evaluate the nature of selection pressures acting on the gene during its evolution. We analyzed both coding and regulatory regions of the DARC gene. The regulatory analysis showed accelerated rates of substitution at several sites near known motifs. Our tests of positive selection in the coding region using maximum likelihood by branch sites and maximum likelihood by codon sites did not yield statistically significant evidence for the action of positive selection. However, the maximum likelihood test in which the gene was subdivided into different structural regions showed that the known binding region for P. vivax/P. knowlesi is under very different selective pressures than the remainder of the gene. In fact, most of the gene appears to be under strong purifying selection, but this is not evident in the binding region. We suggest that the binding region is under the influence of two opposing selective pressures, positive selection possibly exerted by the parasite and purifying selection exerted by chemokines.     

Evolution of P elements in natural populations of Drosophila willistoni and D. sturtevanti

To determine how population structure of the host species affects the spread of transposable elements and to assess the strength of selection acting on different structural regions, we sequenced P elements from strains of Drosophila willistoni and Drosophila sturtevanti sampled from across the distributions of these species. Elements from D. sturtevanti exhibited considerable sequence variation, and similarity among them was correlated to geographic distance between collection sites. By contrast, all D. willistoni elements sampled were essentially identical (pi < 0.2%) and exhibited patterns typical of a recent population expansion. While the canonical P elements sampled from D. sturtevanti appear to be long-time residents in that species, a rapid expansion of a very young canonical P-element lineage is suggested in D. willistoni, overcoming barriers such as large geographical distances and moderate levels of population subdivision. Between-species comparisons reveal selective constraints on P-element evolution, as indicated by significantly different substitution rates in noncoding, silent, and replacement sites. Most remarkably, in addition to replacement sites, selection pressure appears to be strong in the first and third introns and in the 3' and 5' flanking regions.     

The distribution of human genetic diversity: a comparison of mitochondrial, autosomal, and Y-chromosome data

We report a comparison of worldwide genetic variation among 255 individuals by using autosomal, mitochondrial, and Y-chromosome polymorphisms. Variation is assessed by use of 30 autosomal restriction-site polymorphisms (RSPs), 60 autosomal short-tandem-repeat polymorphisms (STRPs), 13 Alu-insertion polymorphisms and one LINE-1 element, 611 bp of mitochondrial control-region sequence, and 10 Y-chromosome polymorphisms. Analysis of these data reveals substantial congruity among this diverse array of genetic systems. With the exception of the autosomal RSPs, in which an ascertainment bias exists, all systems show greater gene diversity in Africans than in either Europeans or Asians. Africans also have the largest total number of alleles, as well as the largest number of unique alleles, for most systems. GST values are 11%-18% for the autosomal systems and are two to three times higher for the mtDNA sequence and Y-chromosome RSPs. This difference is expected because of the lower effective population size of mtDNA and Y chromosomes. A lower value is seen for Y-chromosome STRs, reflecting a relative lack of continental population structure, as a result of rapid mutation and genetic drift. Africa has higher GST values than does either Europe or Asia for all systems except the Y-chromosome STRs and Alus. All systems except the Y-chromosome STRs show less variation between populations within continents than between continents. These results are reassuring in their consistency and offer broad support for an African origin of modern human populations.     

Comparison of craniofacial features of major human groups

Distance analysis and factor analysis, based on Q-mode correlation coefficients, were applied to 23 craniofacial measurements in 1,802 recent and prehistoric crania from major geographical areas of the Old World. The major findings are as follows: 1) Australians show closer similarities to African populations than to Melanesians. 2) Recent Europeans align with East Asians, and early West Asians resemble Africans. 3) The Asian population complex with regional difference between northern and southern members is manifest. 4) Clinal variations of craniofacial features can be detected in the Afro-European region on the one hand, and Australasian and East Asian region on the other hand. 5) The craniofacial variations of major geographical groups are not necessarily consistent with their geographical distribution pattern. This may be a sign that the evolutionary divergence in craniofacial shape among recent populations of different geographical areas is of a highly limited degree. Taking all of these into account, a single origin for anatomically modern humans is the most parsimonious interpretation of the craniofacial variations presented in this study. © 1996 Wiley-Liss, Inc.     

The molecular basis of an avian plumage polymorphism in the wild: a melanocortin-1-receptor point mutation is perfectly associated with the melanic plumage morph of the bananaquit, Coereba flaveola

BACKGROUND: Evolution depends on natural selection acting on phenotypic variation, but the genes responsible for phenotypic variation in natural populations of vertebrates are rarely known. The molecular genetic basis for plumage color variation has not been described in any wild bird. Bananaquits (Coereba flaveola) are small passerine birds that occur as two main plumage variants, a widespread yellow morph with dark back and yellow breast and a virtually all black melanic morph. A candidate gene for this color difference is the melanocortin-1 receptor (MC1R), a key regulator of melanin synthesis in feather melanocytes. RESULTS: We sequenced the MC1R gene from four Caribbean populations of the bananaquit; two populations of the yellow morph and two populations containing both the yellow morph and the melanic morph. A point mutation resulting in the replacement of glutamate with lysine was present in at least one allele of the MC1R gene in all melanic birds and was absent in all yellow morph birds. This substitution probably causes the color variation, as the same substitution is responsible for melanism in domestic chickens and mice. The evolutionary relationships among the MC1R haplotypes show that the melanic alleles on Grenada and St. Vincent had a single origin. The low prevalence of nonsynonymous substitutions among yellow haplotypes suggests that they have been under stabilizing selection, whereas strong selective constraint on melanic haplotypes is absent. CONCLUSIONS: We conclude that a mutation in the MC1R is responsible for the plumage polymorphism in a wild bird population and that the melanic MC1R alleles in Grenada and St. Vincent bananaquit populations have a single evolutionary origin from a yellow allele.     

The STR polymorphism (AAAAT)n within the intron 1 of the tumor protein 53 (TP53) locus in 17 populations of different ethnic groups of Africa, America, Asia and Europe

The STR (AAAAT)n within intron 1 of the TP53 locus was screened in 17 populations from 3 main ethnic groups: Europeans, Asiatics, and Africans, and from the hybrid population of Costa Rica (1968 samples). Three alleles, 126/7 (bp/copies of the repeat), 131/8 and 136/9 were the most prevalent in all populations. Other alleles rarely reached frequencies of 10% or higher. Observed heterozygosities ranged between 0.351 and 0.829. Patterns of diversity fit well with both the geographic origin of the samples and the history of the populations screened. A statistical test suggests that single-step mutational events have been the main mechanism producing new alleles at this locus. Fixation indexes (R(ST)) for this marker showed an effect of population subdivision on divergence only within the Asiatic group; they were insensitive at the level of major ethnic groups as well as within Africans and within Europeans.