Microsatellite data show recent demographic expansions in sedentary but not in nomadic human populations in Africa and Eurasia

The transition from hunting and gathering to plant and animal domestication was one of the most important cultural and technological revolutions in human history. According to archeologists and paleoanthropologists, this transition triggered major demographic expansions. However, few genetic studies have found traces of Neolithic expansions in the current repartition of genetic polymorphism, pointing rather toward Paleolithic expansions. Here, we used microsatellite autosomal data to investigate the past demographic history of 87 African and Eurasian human populations with contrasted lifestyles (nomadic hunter-gatherers, semi-nomadic herders and sedentary farmers). Likely due to the combination of a higher mutation rate and the possibility to analyze several loci as independent replicates of the coalescent process, the analysis of microsatellite data allowed us to infer more recent expansions than previous genetic studies, potentially resulting from the Neolithic transition. Despite the variability in their location and environment, we found consistent expansions for all sedentary farmers, while we inferred constant population sizes for all hunter-gatherers and most herders that could result from constraints linked to a nomadic or semi-nomadic lifestyle and/or competition for land between herders and farmers. As an exception, we inferred expansions for Central Asian herders. This might be linked with the arid environment of this area that may have been more favorable to nomadic herders than to sedentary farmers. Alternatively, current Central Asian herders may descent from populations who have first experienced a transition from hunter-gathering to sedentary agropastoralism, and then a second transition to nomadic herding.     

Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia

Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans and confirmed by meta-analysis of published linkage data. Systematic fine mapping using extended Icelandic pedigrees identified an associated haplotype in the gene neuregulin 1 (NRG1), also known as heuregulin, glial growth factor, NDF43 and ARIA. A 290 kb core at risk haplotype at the 5' end of the gene (HAP(ICE)), defined by five SNPs and two microsatellite polymorphisms was found to be associated with schizophrenia in the Icelandic and Scottish populations. A number of subsequent independent studies have attempted to replicate the association, and while some have been successful, the associated haplotype is not always HAP(ICE). Furthermore, no obviously functional or pathogenic variants have been identified, and the relationship between the gene and schizophrenia has remained inconclusive. To reconcile these conflicting findings and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of 13 published population-based and family-based association studies up to November 2005. We analysed data from the SNP markers SNP8NRG241930, SNP8NRG243177, SNP8NRG221132 and SNP8NRG221533, and the microsatellite markers 478B14-848, 420M9-1395. Across these studies, strong positive association was found for all six polymorphisms. The haplotype analysis also showed significant association in the pooled international populations (OR=1.22, 95% CI 1.15-1.3, P=8 x 10(-10)). In Asian populations, the risk haplotype was focused around the two microsatellite markers, 478B14-848, 420M9-1395 (haplotype block B), and in Caucasian populations with the remaining four SNP markers (haplotype block A). This meta-analysis supports the involvement of NRG1 in the pathogenesis of schizophrenia, but with association between two different but adjacent haplotypes blocks in the Caucasian and Asian populations.     

Searching for the origin of Gagauzes: Inferences from Y‐chromosome analysis

The Gagauzes are a small Turkish‐speaking ethnic group living mostly in southern Moldova and northeastern Bulgaria. The origin of the Gagauzes is obscure. They may be descendants of the Turkic nomadic tribes from the Eurasian steppes, as suggested by the “Steppe” hypothesis, or have a complex Anatolian‐steppe origin, as postulated by the “Seljuk” or “Anatolian” hypothesis. To distinguish these hypotheses, a sample of 89 Y‐chromosomes representing two Gagauz populations from the Republic of Moldova was analyzed for 28 binary and seven STR polymorphisms. In the gene pool of the Gagauzes a total of 15 Y‐haplogroups were identified, the most common being I‐P37 (20.2%), R‐M17 (19.1%), G‐M201 (13.5%), R‐M269 (12.4%), and E‐M78 (11.1%). The present Gagauz populations were compared with other Balkan, Anatolian, and Central Asian populations by means of genetic distances, nonmetric multidimentional scaling and analyses of molecular variance. The analyses showed that Gagauzes belong to the Balkan populations, suggesting that the Gagauz language represents a case of language replacement in southeastern Europe. Interestingly, the detailed study of microsatellite haplotypes revealed some sharing between the Gagauz and Turkish lineages, providing some support of the hypothesis of the “Seljuk origin” of the Gagauzes. The faster evolving microsatellite loci showed that the two Gagauz samples investigated do not represent a homogeneous group. This finding matches the cultural and linguistic heterogeneity of the Gagauzes well, suggesting a crucial role of social factors in shaping the Gagauz Y‐chromosome pool and possibly also of effects of genetic drift. Am. J. Hum. Biol., 2009. © 2008 Wiley‐Liss, Inc.     

A unique origin and multistep process for the generation of expanded DRPLA triplet repeats

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder associated with the expansion of a CAG repeat at chromosome band 12p13. Epidemiological studies have demonstrated an increased prevalence of DRPLA in Japan, although several DRPLA kindreds of non-Japanese ancestry have been identified. To define the molecular basis for this geographic variation in prevalence, we have analyzed haplotypes around the repeat in several different ethnic groups. Two intragenic biallelic polymorphisms distinguished three haplotypes, each of which formed a predominant haplotype found in the three major racial populations. All the expanded repeats of Japanese and Caucasian patients studied were associated with a particular haplotype, which otherwise was associated with longer repeats commonly found in Asians. Our results support a multi-step model for repeat expansion, and suggest that expanded DRPLA repeats may have evolved from an ancient chromosomal haplotype of Asian origin. We also propose that a combination of a highly polymorphic microsatellite marker with relatively stable biallelic markers in a range of PCR amplification is a powerful tool for studies on human genome diversity, which may reveal the ancient human migration and the formation of ethnic groups.      

Microsatellite markers reveal genetic differentiation among populations of Sclerotinia sclerotiorum from Australian canola fields

Eight microsatellite markers were applied to 154 Sclerotinia sclerotiorum isolates from four Australian canola fields, to determine the extent of genetic variation and differentiation in populations of this pathogen. A total of 82 different haplotypes were identified and in each population many haplotypes were unique. Mycelial compatibility grouping, a phenotypic marker system controlled by multiple loci, was often associated with groups of identical or closely related microsatellite haplotypes. Genotypic diversity ranged from 36% to 80% of maximum in the four populations, and gene diversity ranged from 0.23 to 0.79. Genotypic disequilibrium analyses on each of the four populations suggested that both clonal and sexual reproduction contributed to population structure. Analyses based on genetic diversity and fixation indices demonstrated a moderate to high level of differentiation (R_ST=0.16–0.33, F_ST=0.18–0.23) between populations from New South Wales and those from Victoria. Despite this genetic diversity, most isolates did not vary in virulence on canola leaves.     

In the heartland of Eurasia: the multilocus genetic landscape of Central Asian populations

Located in the Eurasian heartland, Central Asia has played a major role in both the early spread of modern humans out of Africa and the more recent settlements of differentiated populations across Eurasia. A detailed knowledge of the peopling in this vast region would therefore greatly improve our understanding of range expansions, colonizations and recurrent migrations, including the impact of the historical expansion of eastern nomadic groups that occurred in Central Asia. However, despite its presumable importance, little is known about the level and the distribution of genetic variation in this region. We genotyped 26 Indo-Iranian- and Turkic-speaking populations, belonging to six different ethnic groups, at 27 autosomal microsatellite loci. The analysis of genetic variation reveals that Central Asian diversity is mainly shaped by linguistic affiliation, with Turkic-speaking populations forming a cluster more closely related to East-Asian populations and Indo-Iranian speakers forming a cluster closer to Western Eurasians. The scattered position of Uzbeks across Turkic- and Indo-Iranian-speaking populations may reflect their origins from the union of different tribes. We propose that the complex genetic landscape of Central Asian populations results from the movements of eastern, Turkic-speaking groups during historical times, into a long-lasting group of settled populations, which may be represented nowadays by Tajiks and Turkmen. Contrary to what is generally thought, our results suggest that the recurrent expansions of eastern nomadic groups did not result in the complete replacement of local populations, but rather into partial admixture.     

Next-generation sequencing characterization of HLA in multi-generation families of Kuwaiti descent

The frequency of HLA genes in one population may not accurately represent frequencies in other populations. In this study, we characterized extended human leukocyte antigen (HLA) haplotypes in several families of Kuwaiti descent by high-resolution typing using next-generation technology. A total 81 members (including patients and related donors) from 21 families were enrolled. No haplotypes were shared among multiple families. Of 77 haplotypes identified, 23 were not listed in the HaploStats database. Two haplotypes were most common in African Americans, six in Asian Pacific Islanders, three in Caucasians, three in Hispanics, and three in Native Americans. The remaining identified haplotypes were not among the most common 200 HLA haplotypes in any of the five major populations. This cohort had 202 (19%) unique alleles, including 20 rare alleles, 16 very rare alleles, and 2 novel ones. Furthermore, no frequency data were available for 30% (23/77) of the observed haplotypes, and 6% (3/49) of B?～?C blocks identified were not available in the HaploStats database. Kuwaiti individuals carry unique HLA haplotypes that are not shared by the majority of individuals historically reported to the US National Marrow Donor Program registry.     

Haplotype Structure of FSHB, the Beta-Subunit Gene for Fertility-Associated Follicle-Stimulating Hormone: Possible Influence of Balancing Selection

Follicle-stimulating hormone (FSH) is essential for human reproduction. The unique functions of this hormone are provided by the FSH receptor-binding beta-subunit encoded by the FSHB gene. Resequencing and genotyping of FSHB in three European, two Asian and one African population, as well as in the great apes (chimpanzee, gorilla, orangutan), revealed low diversity and significant excess of polymorphisms with intermediate frequency alleles. Statistical tests for FSHB showed deviations from neutrality in all populations suggesting a possible effect of balancing selection. Two core haplotypes were identified (carried by 76-96.6% of each population's sample), the sequences of which are clearly separated from each other. As fertility most directly affects an organism's fitness, the carriers of these haplotypes have apparently had more success in human history to contribute to the next generation. There is a preliminary observation suggesting that the second most frequent FSHB haplotype may be associated with rapid conception success in females. Interestingly, the same haplotype is related to an ancestral FSHB variant shared with the ancestor of the great apes. The determination of the functional consequence of the two core FSHB variants may have implications for understanding and regulating human fertility, as well as in assisting infertility treatments.     

Y-chromosomal SNPs in Finno-Ugric-speaking populations analyzed by minisequencing on microarrays

An increasing number of single nucleotide polymorphisms (SNPs) on the Y chromosome are being identified. To utilize the full potential of the SNP markers in population genetic studies, new genotyping methods with high throughput are required. We describe a microarray system based on the minisequencing single nucleotide primer extension principle for multiplex genotyping of Y-chromosomal SNP markers. The system was applied for screening a panel of 25 Y-chromosomal SNPs in a unique collection of samples representing five Finno--Ugric populations. The specific minisequencing reaction provides 5-fold to infinite discrimination between the Y-chromosomal genotypes, and the microarray format of the system allows parallel and simultaneous analysis of large numbers of SNPs and samples. In addition to the SNP markers, five Y-chromosomal microsatellite loci were typed. Altogether 10,000 genotypes were generated to assess the genetic diversity in these population samples. Six of the 25 SNP markers (M9, Tat, SRY10831, M17, M12, 92R7) were polymorphic in the analyzed populations, yielding six distinct SNP haplotypes. The microsatellite data were used to study the genetic structure of two major SNP haplotypes in the Finns and the Saami in more detail. We found that the most common haplotypes are shared between the Finns and the Saami, and that the SNP haplotypes show regional differences within the Finns and the Saami, which supports the hypothesis of two separate settlement waves to Finland.     

Y-chromosome variation in Tajiks and Iranians

Aim: The purpose of this study was to characterize Y-chromosome diversity in Tajiks from Tajikistan and in Persians and Kurds from Iran.

Method: Y-chromosome haplotypes were identified in 40 Tajiks, 77 Persians and 25 Kurds, using 12 short tandem repeats (STR) and 18 binary markers.

Results: High genetic diversity was observed in the populations studied. Six of 12 haplogroups were common in Persians, Kurds and Tajiks, but only three haplogroups (G-M201, J-12f2 and L-M20) were the most frequent in all populations, comprising together ～ 60% of the Y-chromosomes in the pooled data set. Analysis of genetic distances between Y-STR haplotypes revealed that the Kurds showed a great distance to the Iranian-speaking populations of Iran, Afghanistan and Tajikistan. The presence of Indian-specific haplogroups L-M20, H1-M52 and R2a-M124 in both Tajik samples from Afghanistan and Tajikistan demonstrates an apparent genetic affinity between Tajiks from these two regions.

Conclusions: Despite the marked similarities between Y-chromosome gene pools of Iranian-speaking populations, there are differences between them, defined by many factors, including geographic and linguistic relationships.     

Population genetic diversity of the NAT2 gene supports a role of acetylation in human adaptation to farming in Central Asia

The arylamine N-acetyltransferase 2 (NAT2) enzyme detoxifies a wide spectrum of naturally occurring xenobiotics including carcinogens and drugs. Variation at the NAT2 gene has been linked to the human acetylation capacity, either 'slow' or 'fast', which modifies susceptibility to cancer and adverse drug reactions. We investigated the possible influence of natural selection in shaping the acetylation phenotype and the NAT2 gene variability in six Central Asian populations, who are either long-term sedentary agriculturalists (two Tajik populations), recent sedentary agriculturalists (Kazakhs, Uzbeks) or nomad pastoralists (two Kirghiz populations). To this end, we sequenced the entire NAT2 coding exon, as well as genotyping nine intergenic SNPs covering a 200-kb region. Our results revealed that the two Tajik populations exhibited significantly higher proportions of slow acetylators than the nomadic populations. In addition, sequence-based neutrality tests yielded significantly positive values in Central Asian populations following an agriculturalist lifestyle, due to an excess of haplotypes at intermediate frequencies. Taken together, our data suggest that balancing selection, and/or directional selection on standing low-frequency alleles, have shaped NAT2 genetic diversity and the human acetylation phenotype in Central Asian agriculturalists. These results further support the hypothesis that a major transition in human lifestyle, such as the emergence of farming has dramatically changed human chemical environments and the selective pressures they imposed.     

Molecular analysis of haemoglobin E in Southeast Asian populations

Haemoglobin (Hb) E is the most common Hb variant in Asia where its gene frequency approaches 0.3 in some areas. We studied genetic background of Hb E genes among Southeast Asian populations. This study examined β-globin gene haplotypes linked to haemoglobin E (Hb E) in diverse groups of Southeast Asian populations. The study was conducted on southern Thai (22 alleles), Cambodian (84 alleles), Laotian (120 alleles), Vietnamese (87 alleles) and Burmese (one allele) subjects. Results were compared with those of previous studies in northeast Thailand, the Yunnan of China, West India and Europe. Ten different haplotypes were observed. The four most common haplotypes were haplotypes 1 (–?+?–?+?+?+?–) and 2 (+?–?–?–?–?+?–) on chromosomes with framework 2 and haplotypes 6 (–?+?–?+?+?–?+) and 7 (+?– – – – –?+) on chromosomes with framework 3 variety. Phylogenetic analysis indicated that haplotype 1 is a relatively recent haplotype found in all populations, whereas haplotype 6 is found predominately in Cambodians. The results indicate that at least two genetic origins of Hb E are responsible for the high prevalence and spread of Hb E among Southeast Asian populations.     

Y-Specific DNA polymorphisms of the YAP element and the locus DYS19 in the Korean population

The Y Alu polymorphic (YAP) element (DYS287) and the Y-linked tetranucleotide microsatellite locus DYS19 were examined in samples from a total of 455 unrelated males in the Korean population. The frequency of the YAP ⁺ allele was found to be 1.3% (6/455) in the Korean population. These results are consistent with previous reports that showed the YAP element to be absent in most Asian populations, with the exception of the high frequency of the YAP ⁺ allele in the Japanese population. All five common alleles at the DYS19 locus were identified in this study. The C allele was the most frequent (197/455), followed by the D (119/455), B (78/455), E (41/455), and A (20/455) alleles. Seven combination haplotypes (DYS287/DYS19) were found, and the mean combination haplotype diversity in the Korean population appeared to be 0.71. Based on results of these two loci, Japanese and Korean populations may share some common genetic structure that could reflect recent gene flow and some amount of admixture of Y chromosomes between these two populations. Received: March 18, 1998 / Accepted: May 19, 1998     

Genetic variability and linkage disequilibrium within the HLA-DP region: analysis of 15 different populations

In order to understand the forces governing the evolution of the genetic diversity in the HLA-DP molecule, polymerase chain reaction (PCR)-based methods were used to characterize genetic variation at the DPA1 and DPB1 loci encoding this heterodimer on 2,807 chromosomes from 15 different populations including individuals of African, Asian, Amerindian, Indian and European origin. These ethnically diverse samples represent a variety of population substructures and include small, isolated populations as well as larger, presumably admixed populations. Ten DPA1 and 39 DPB1 alleles were identified and observed on 87 distinct DP haplotypes, 34 of which were found to be in significant positive linkage disequilibrium in at least one population. Some haplotypes were found in all ethnic groups while others were confined to a single ethnic group or population. Strong positive global linkage disequilibrium (Wn) between DPA1 and DPB1 was present in all 15 populations. The African populations displayed the lowest values of Wn whereas the Amerindian populations displayed near absolute disequilibrium. Analysis of the distribution of haplotypes using the normalized deviate of the Ewens-Watterson homozygosity statistic, F, suggests that DP haplotypes encoding the functional heterodimer are subject to much lower degrees of balancing selection than other loci within the HLA region. Finally, neighbor joining tree analyses demonstrate the power of haplotype diversity for inferring the relationships between the different populations.     

Haplotypic relationship between SNP and microsatellite markers at the NOS2A locus in two populations

The density of genetic markers required for successful association mapping of complex diseases depends on linkage disequilibrium (LD) between non-functional markers and functional variants. The haplotypic relationship between stable markers and potentially unstable but highly informative markers (e.g. microsatellites) indicates that LD might be maintained over considerable genetic distance in non-African populations, supporting the use of such 'mixed marker haplotypes' in LD-based mapping, and allowing inferences to be drawn about human origins. We investigated sequence variation in the proximal 2.6 kb of the inducible nitric oxide synthase (NOS2A) promoter and the relationship between SNP haplotypes and a pentanucleotide microsatellite (the 'NOS2A(-2.6) microsatellite') in Gambians and UK Caucasians. UK Caucasians exhibited a subset of sequence diversity observed in Gambians, sharing four of 11 SNPs and a similar haplotypic structure. Five SNPs were found in the sequence of interspersed repetitive DNA elements. In both populations, there was dramatic loss of LD between SNP haplotypes and microsatellite alleles across a very short physical distance, suggesting a high intrinsic mutation rate of the NOS2A(-2.6) microsatellite, the SNP haplotypes are relatively ancient, or that this was a region of frequent recombination. Understanding locus- and population-specific LD is essential when designing and interpreting genetic association studies.     

The Y-chromosome short tandem repeats variation within haplogroup E3b: evidence of recurrent mutation in SNP.

Haplogroup E3b is defined by a single nucleotide mutation (SNP) in locus M35 and is found at high frequency (more than 35%) in populations from North Africa with a heterogeneous distribution. On the basis of compilation of 553 Y-chromosomes from Europe and 633 from sub-Saharan Africa we selected 130 individuals belonging to haplogroup E3b and characterized subhaplogroups according to the Y-Chromosome Consortium nomenclature. Y-chromosome haplotypes can be defined using short tandem repeats (STR). The use of STRs makes it possible to measure diversity and estimate age coalescence. Significant differences on frequencies of Y-chromosome STR loci were found among the E3b subhaplogroups and the same was observed when haplotype frequencies were considered. Some mutations in SNPs were detected when comparing E3b subhaplogroups with the correspondent STR haplotypes. These results show that the mutation rate for some SNPs could be higher than previously thought and also that it is important to associate both haplotype and haplogroup in Y-chromosome studies.     

Microsatellite typing for DRB1 alleles: application to the analysis of HLA associations with rheumatoid arthritis

The current methods for molecular typing of HLA-DR alleles incur a substantial financial burden when performing large population studies. In the current study, we aimed to provide much less expensive typing approach with high predictability for DRB1 genotype. We have used a panel of three microsatellite markers in the class II region (D6S2666, D6S2665 and D6S2446) for genotyping and haplotype reconstruction in a total of 1687 Caucasian (1313 RA patients and 374 controls) and 1364 Korean individuals (744 RA patients and 620 controls), all of whom were previously genotyped for DRB1. We found that a total of 88.4 and 87.4% of all observed three-marker haplotypes could determine the DR type with a positive predictive value >0.8 with high sensitivity and specificity. There was a high degree of haplotype conservation when comparing Caucasian and Asian populations. Interestingly, we found that the majority of DRB1*09 and DRB1*10 alleles share a common three-marker haplotype in both Caucasian and Asian populations. This is unexpected, since these two alleles are found on very different haplotype families. In addition, these two alleles are both associated with rheumatoid arthritis, making the elucidation of these haplotype relationships potentially important for understanding disease susceptibility.     

Phylogeography of the Y‐chromosome haplogroup C in northern Eurasia

To reconstruct the phylogenetic structure of Y‐chromosome haplogroup (hg) C in populations of northern Eurasia, we have analyzed the diversity of microsatellite (STR) loci in a total sample of 413 males from 18 ethnic groups of Siberia, Eastern Asia and Eastern Europe. Analysis of SNP markers revealed that all Y‐chromosomes studied belong to hg C3 and its subhaplogroups C3c and C3d, although some populations (such as Mongols and Koryaks) demonstrate a relatively high input (more than 30%) of yet unidentified C3* haplotypes. Median joining network analysis of STR haplotypes demonstrates that Y‐chromosome gene pools of populations studied are characterized by the presence of DNA clusters originating from a limited number of frequent founder haplotypes. These are subhaplogroup C3d characteristic for Mongolic‐speaking populations, “star cluster” in C3* paragroup, and a set of DYS19 duplicated C3c Y‐chromosomes. All these DNA clusters show relatively recent coalescent times (less than 3000 years), so it is probable that founder effects, including social selection resulting in high male fertility associated with a limited number of paternal lineages, may explain the observed distribution of hg C3 lineages.