Polymorphisms at locus D1S80 and other hypervariable regions in the analysis of Eastern European ethnic group relationships

BACKGROUND: It has been hypothesized that, whereas many loci are used to generate phylogenetic relationships, the utilization of those that yield the most information could increase the accuracy of any multilocus phylogenetic reconstruction. Among these is the D1S80 hypervariable minisatellite region, which has been shown to be highly polymorphic globally, and it was of interest to compare the nearest neighbours and distant populations of Eastern Europe using the D1S80 polymorphism. AIM: The study evaluated the capacity of the D1S80 locus to discriminate between populations from different ethnic groups in Russia and the Republic of Belarus, revealing the polymorphism parameters of the populations studied. SUBJECTS AND METHODS: Hypervariable D1S80 minisatellite polymorphism was studied in 15 populations, belonging to six distinct ethnic groups from the Russian Federation (Russians, Komis, Maris, Udmurts, Kalmyks, and Yakuts) and the Republic of Belarus (Byelorussians). The data were analysed with other results reported for D1S80 polymorphism among Eastern Europeans, and were analysed together with those previously reported for Eastern European populations for the 3'ApoB, DMPK, DRPLA, and SCA1 hypervariable loci. Genetic diversity analysis was carried out using multidimensional scaling (MDS) of Nei's genetic distances. RESULTS: The Eastern Slavonic populations (Russians, Ukrainians, and Byelorussians) are closely associated, and outermost from populations of Asian origin (Kalmyks and Yakuts). The populations that inhabit the Volga-Ural region (Udmurt, Komi, Mari, and Bashkir ethnic groups) revealed intermediate characteristics. CONCLUSION: The clustering of populations demonstrated here using D1S80 alone coincides with the analysis of five hypervariable region (HVR) loci, and is consistent with linguistic, geographic, and ethnohistorical data. These results are in agreement with most studies of mtDNA, Y-chromosomal, and autosomal DNA diversity in Eastern Europe. The D1S80 locus is convenient for population analyses, and may be used as part of a set of similar markers, which should allow the easy resolution of small differences in population structures.     

Polymorphisms at locus D1S80 and other hypervariable regions in the analysis of Eastern European ethnic group relationships

Background: It has been hypothesized that, whereas many loci are used to generate phylogenetic relationships, the utilization of those that yield the most information could increase the accuracy of any multilocus phylogenetic reconstruction. Among these is the D1S80 hypervariable minisatellite region, which has been shown to be highly polymorphic globally, and it was of interest to compare the nearest neighbours and distant populations of Eastern Europe using the D1S80 polymorphism.

Aim: The study evaluated the capacity of the D1S80 locus to discriminate between populations from different ethnic groups in Russia and the Republic of Belarus, revealing the polymorphism parameters of the populations studied.

Subjects and methods: Hypervariable D1S80 minisatellite polymorphism was studied in 15 populations, belonging to six distinct ethnic groups from the Russian Federation (Russians, Komis, Maris, Udmurts, Kalmyks, and Yakuts) and the Republic of Belarus (Byelorussians). The data were analysed with other results reported for D1S80 polymorphism among Eastern Europeans, and were analysed together with those previously reported for Eastern European populations for the 3′ApoB, DMPK, DRPLA, and SCA1 hypervariable loci. Genetic diversity analysis was carried out using multidimensional scaling (MDS) of Nei's genetic distances.

Results: The Eastern Slavonic populations (Russians, Ukrainians, and Byelorussians) are closely associated, and outermost from populations of Asian origin (Kalmyks and Yakuts). The populations that inhabit the Volga–Ural region (Udmurt, Komi, Mari, and Bashkir ethnic groups) revealed intermediate characteristics.

Conclusion: The clustering of populations demonstrated here using D1S80 alone coincides with the analysis of five hypervariable region (HVR) loci, and is consistent with linguistic, geographic, and ethnohistorical data. These results are in agreement with most studies of mtDNA, Y-chromosomal, and autosomal DNA diversity in Eastern Europe. The D1S80 locus is convenient for population analyses, and may be used as part of a set of similar markers, which should allow the easy resolution of small differences in population structures.     

TP53 polymorphisms and haplotypes in South Amerindians and neo-Brazilians

To evaluate the genetic diversity of Brazilian populations and contribute to the knowledge of their evolutionary history this study investigated three TP53 polymorphisms (BstUI and MspI RFLPs in exon 4 and intron 6, respectively, and a 16 bp duplication in intron 3). The populations studied were: 114 Amerindians from five Brazilian Indian tribes (Gavi?o, Surui, Zoró, Wai-Wai and Xavante), 95 Euro-Brazilians and 70 Afro-Brazilians. The polymorphisms were all analysed using PCR amplifications. Gene frequencies and haplotype prevalences were calculated using the ARLEQUIN software. The genetic affinities of these groups with other world populations were estimated by the D(A) distance and neighbour joining method, using the NJBAFD computer program. Neo-Brazilians (immigrants from Europe and Africa) generally presented more variability than Amerindians, Afro-Brazilians being the most variable population. Among Amerindians, Gavi?o is the only group polymorphic for the three markers. Wai-Wai showed variability in BstUI and MspI RFLPs, while the other tribes were monomorphic for the 16 bp A1 and MspI A2 alleles. A rare haplotype (1-2-1) was verified among the Wai-Wai. This haplotype was previously described in a Chinese sample only, but with low frequency. Therefore, either this combination was lost in the other tribes by genetic drift, recombination, or other factor, or it occurs in the Wai-Wai and Chinese by independent events. The Gavi?o also presented a haplotype (2-1-1) not observed in the other Amerindians; but since it is present in Euro- and Afro-Brazilians. its occurrence there is probably due to interethnic admixture. The relationships of several world populations obtained using TP53 indicates that this marker is very efficient in clustering populations of the same ethnic group.     

TP53 polymorphisms and haplotypes in South Amerindians and neo-Brazilians

To evaluate the genetic diversity of Brazilian populations and contribute to the knowledge of their evolutionary history this study investigated three TP53 polymorphisms (BstUI and MspI RFLPs in exon 4 and intron 6, respectively, and a 16bp duplication in intron 3). The populations studied were: 114 Amerindians from five Brazilian Indian tribes (Gavião, Surui, Zoró, Wai-Wai and Xavante), 95 Euro-Brazilians and 70 Afro-Brazilians. The polymorphisms were all analysed using PCR amplifications. Gene frequencies and haplotype prevalences were calculated using the ARLEQUIN software. The genetic affinities of these groups with other world populations were estimated by the D_A distance and neighbour joining method, using the NJBAFD computer program. Neo-Brazilians (immigrants from Europe and Africa) generally presented more variability than Amerindians, Afro-Brazilians being the most variable population. Among Amerindians, Gavião is the only group polymorphic for the three markers. Wai-Wai showed variability in BstUI and MspI RFLPs, while the other tribes were monomorphic for the 16bp A1 and MspI A2 alleles. A rare haplotype (1-2-1) was verified among the Wai-Wai. This haplotype was previously described in a Chinese sample only, but with low frequency. Therefore, either this combination was lost in the other tribes by genetic drift, recombination, or other factor, or it occurs in the Wai-Wai and Chinese by independent events. The Gavião also presented a haplotype (2-1-1) not observed in the other Amerindians; but since it is present in Euro- and Afro-Brazilians, its occurrence there is probably due to interethnic admixture. The relationships of several world populations obtained using TP53 indicates that this marker is very efficient in clustering populations of the same ethnic group.     

D1S80 distribution in world populations with new data from the UK and the Indian sub-continent

BACKGROUND: Highly polymorphic genetic markers including variable number of tandem repeats (VNTRs), amplified fragment length polymorphisms (AMP-FLPs) and short tandem repeats (STRs) have been used successfully in disease diagnostics, forensics, paternity analysis and population diversity studies. The D1S80 locus has been extensively investigated in many populations but studies on the UK and Indian subcontinent populations are limited. AIM: This study aims to enlarge our understanding of genetic variation at the D1S80 locus in the populations of the UK and the Indian subcontinent. Also, the spectrum of genetic variation at this locus in world populations is analysed. SUBJECTS AND METHODS: Six geographically and ethnically diverse populations were genotyped for the D1S80 locus using the polymerase chain reaction (PCR) technique. Two UK populations were from the East Midlands and North East England, while Brahmins, Parsis, Sinhalese and Moors represented the Indian subcontinent populations. In addition, allele frequency data of the present study were compared with 78 world populations using different methods of multivariate analyses to document level and extent of genetic diversity. RESULTS: All study populations were in Hardy-Weinberg equilibrium. A trimodal distribution (alleles 18, 24 and 31) was observed in four populations (North East England, East Midlands, Brahmins and Parsis). The Sinhalese and the Moors had different trimodal distributions. The overall heterozygosity and the level of variation are comparable to many Caucasian populations. Multivariate analyses (correspondence analysis and multidimensional scaling analysis) provided similar results in differentiation of major ethnic population groups. CONCLUSIONS: Since D1S80 variation shows considerable homogeneity within a given ethnic group, but marked variation among them, it is a useful anthropological marker for the differentiation of these populations.     

Apolipoprotein B 3'-VNTR polymorphism in Eastern European populations

Apolipoprotein B 3' (3' ApoB) minisatellite polymorphism was studied in healthy unrelated individuals from the Russian Federation and the Republic of Belarus, in 10 populations from five ethnic groups: Russians, Byelorussians, Adygeis, Kalmyks and Yakuts. The analysis was carried out using PCR and electrophoresis followed by silver staining. Overall, 25 alleles of the 3' ApoB minisatellite, ranging from 25 to 55 repeats, were detected. Heterozygosity indices were high and varied from 0.73 to 0.84. The distributions of alleles of this minisatellite in the Caucasoid populations (Russians, Byelorussians and Adygeis) had a bimodal character, whereas that for Mongoloid populations (Kalmyks and Yakuts) had a unimodal distribution. Nei's genetic distances between the populations studied and some reference populations of Europe and Asia were estimated. Despite their allele distribution homogeneity, different East Slavonic ethnic groups were clearly resolved by multidimensional analyses. The East Slavonic and Adygei populations revealed a high similarity with European Caucasoids. The Mongoloid populations (Kalmyks and Yakuts) were considerably different from those of the European Caucasoid populations, but were similar to other Asian Mongoloid populations. The results demonstrate the variability of 3' ApoB minisatellite polymorphism not only in distant populations but also, to a certain extent, in genetically relative ones.     

Use of short tandem repeats loci to study the genetic structure of several populations from Zulia State, Venezuela.

Genetic relationships between populations can be studied by comparing genotypic and allelic similarities. This investigation aims to demonstrate that selected autosomal microsatellite markers could be used to study the genetic structures of different populations living in northwest Venezuela, in Zulia State. Seven autosomal systems (CSF1PO, TPOX, TH01, vWA, D7S820, D13S317, and D5S818) were tested by PCR in a multiplex format on 688 different chromosomes from unrelated individuals living in Maracaibo, "Isla de Toas," and "San José de Heras," and from two Amerindian populations from the "Sierra de Perijá," Barí' and Yukpa. Allele frequencies, Hardy-Weinberg equilibria, genetic distances, phylogenetic trees, and ethnic admixtures were estimated. The study shows the existence of a clear genetic difference among these populations in accordance with their historic evolution. The populations of Maracaibo and "Isla de Toas" showed a triracial origin, with a large European contribution, followed by an Amerindian component and a small African component. The indigenous groups, Barí' and Yukpa, showed exclusively an Amerindian component, and "San José de Heras" showed only an African component. These results indicate that microsatellite markers are useful for molecular anthropology in a regional and worldwide context and provide important genetic information about contemporary populations of Venezuela.     

Comparative high-resolution analysis of linkage disequilibrium and tag single nucleotide polymorphisms between populations in the vitamin D receptor gene

A genome-wide map of single nucleotide polymorphisms (SNP) and a pattern of linkage disequilibrium (LD) between their alleles are being established in three main ethnic groups. An important question is the applicability of such maps to different populations within a main ethnic group. Therefore, we have developed high-resolution SNP, haplotype and LD maps of vitamin D receptor gene region in large samples from five populations. Comparative analysis reveals that the LD patterns are identical in all four European populations tested with two small regions of 1.3 and 5.7 kb at which LD is disrupted completely resulting in three block-like regions over which there is significant and extensive LD. In an African population the pattern is similar, but two additional LD-breaking spots are also apparent. This LD pattern suggests combined action of recombination hotspots and founder effects, but cannot be explained by random recombination and genetic drift alone. Direct comparison indicates that the tag SNPs selected in one European population effectively predict the non-tag SNPs in the other Europeans, but not in the Gambians, for this region.     

TP53 polymorphisms and lung cancer risk: a systematic review and meta-analysis

To examine the risk of lung cancer associated with the codon 72, intron 6 and intron 3 TP53 polymorphisms a meta-analysis of published case-control studies was undertaken. The principle outcome measure was the odds ratio (OR) for the risk of lung cancer using homozygosity of the 'wild-type allele' as the reference group. Data from 13 studies detailing the relationship between lung cancer and the codon 72 polymorphism of TP53 and three studies examining the intron 3 and 6 polymorphisms of TP53 were analysed. The ORs of lung cancer associated with the Pro-Pro and Pro-carrier genotypes of codon 72 were 1.18 [95% confidence interval (CI) 0.99-1.41] and 1.02 (95% CI 0.86-1.20), respectively. The ORs of lung cancer associated with homozygous and variant allele carrier genotypes of the intron 6 (MspI RFLP) polymorphism were 1.13 (95% CI 0.55-2.27) and 1.30 (95% CI 0.75-2.26) and of the intron 3 (16 bp duplication) polymorphism were 1.50 (95% CI 0.76-2.97) and 1.11 (95% CI 0.53-2.35), respectively. Although polymorphic variations in TP53 represent attractive candidate susceptibility alleles for lung cancer the results from this analysis provide little support for this hypothesis. Additional well-designed studies based on sample sizes commensurate with the detection of small genotypic risks may allow a more definitive conclusion.     

VNTR Locus D1S80: Application to the study of a mixed Venezuelan sample

The D1S80 locus in 122 individuals from Maracaibo, Venezuela, was studied to verify the genetic relationship of this sample with 32 other reported world populations derived from different ethnic groups. All analyses reveal that the Venezuelan sample has a main European genetic contribution, followed by contribution from Amerindians, and a small contribution of Africans. The population of Maracaibo has a high level of heterozygosity, as expected for populations with an important level of recent admixture. Am. J. Hum. Biol. 12:616–622, 2000. © 2000 Wiley-Liss, Inc.     

Significance of intron 6 sequence variations in the TP53 gene in Li-Fraumeni syndrome

Many polymorphisms have been reported in the TP53 gene. Some of these are within the coding region, and may affect the function of the p53 protein, others are within introns or non-coding regions, and their significance is unclear. Recently, a number of publications have claimed that polymorphisms within intron 6 are responsible for inherited predisposition to childhood malignancies, familial breast cancer, and Li-Fraumeni syndrome (LFS). We find no evidence for intron 6 sequence variants predisposing to LFS in our cohort of families and, furthermore, we show that some of the conclusions of other groups cannot be supported by data from our analysis.     

Haplotype Structure of TP53 Locus in Indian Population and Possible Association with Head and Neck Cancer

It has been proposed that a constellation of three TP53 polymorphisms (intron 3 16 bp duplication, codon 72 BstUI, and intron 6 Nci I RFLP at nt 13494) constitute a haplotype predictive of increased cancer risk. We have estimated the allele frequency of these polymorphisms in three endogamous Indian ethnic populations from three different geographic locations (viz. Iyer from south India, Brahmin from central India and Mahishya from eastern India), as well as in head and neck squamous cell carcinoma (HNSCC) patients, and in ethnically matched normal individuals from the eastern region of India. The genotype distributions and allele frequencies of the three polymorphisms in all but one population, as well as in patients, showed a good fit to Hardy‐Weinberg equilibrium. Strong linkage disequilibria were observed between all loci in every population examined, except for the 16bp‐Nci I haplotype in the Mahishya population. The Mahishya population differed significantly from the other two populations with respect to differences in allele frequency and haplotype frequency. Although there were no significant differences in genotypic frequency at any of the loci between HNSCC patients and the matched control population, the minor allele frequency of codon 72 and intron 3 16 bp polymorphisms showed significant variation. Variation in overall haplotype frequency between patients and normal individuals was significant (p = 0.036) when two rare haplotypes 2‐1‐2 and 1‐2‐1 were combined. The rare haplotype 2‐1‐2 was found to be modestly over represented in HNSCC patients as compared to normal individuals.     

Genetic variability in autochthonous Basques from Guipuzcoa: a view from MHC microsatellites

Five short tandem repeats (STRs) located at human chromosome 6 were analysed in 97 autochthonous Basques from Guipuzcoa (northern Spain), with the aim of assessing the genetic relationships of Basques at a European scale, based on the variability of the major histocompatibility complex (MHC) region, and comparing the phylogenetic information obtained from STRs, and from HLA class I genes (HLA-A and HLA-B) for the same set of European populations. The integrative approach was focused on D6S265 and D6S2792, according to availability of population databases. F_ST genetic distances obtained from STRs and from HLA loci were very similar, thereby describing a comparable pattern of genetic structuring among the European populations. These findings were supported by results of the Mantel test of matrix correspondence (r = 0.796, P = 0.0022) and by significant correlations between the first two F_ST eigenvectors of STRs and HLA genes. Coinciding with previous phylogenetic studies, Basques showed substantial genetic differentiation within the European context, probably as a result of the impact of random genetic drift and high inbreeding levels for extended periods of isolation even from adjacent populations. Analysis of the geographical distribution of the allele frequencies revealed a great number of latitudinal frequency clines in both the MHC STRs and the HLA class I genes, which supports the notion of the post-glacial resettlement of Europe being a crucial factor in the genetic make-up of Europeans. Our results indicate that analysing the genetic variability of MHC microsatellites could be a suitable strategy in evaluating the role of evolutionary forces such as natural selection (because of genetic hitchhiking effect), genetic drift and gene flow in the maintenance of polymorphism at the MHC region, because STRs can efficiently complement the genetic information obtained from HLA genes.     

TP53 and breast cancer

The TP53 gene (p53) is found altered in breast carcinomas in approximately 20-40% of all cases depending on tumor size and stage of the disease. It seems to be an early event in breast tumorigenesis. Several polymorphisms in the TP53 gene have been detected and their possible roles in breast cancer risk and association to type of cancer developed are discussed. The different mutation spectra seen in geographical and ethnic populations may be used to identify environmental exposure contributing to breast cancer development. The role of TP53 mutation as a prognostic marker is reviewed as well as its role as a predictor for therapy response. All data available on TP53 mutation analyses of human breast carcinomas, as well data from transgenic animal studies and experimental cell studies, support an important role for TP53 in mammary carcinogenesis.     

Novel polymorphisms in the IL-10 related AK155 gene (chromosome 12q15)

AK155 is a recently discovered cytokine distantly related to IL-10. Its gene is located on chromosome 12q15, a region that is likely to harbour susceptibility genes for autoimmune and allergic diseases. We provide here identification and characterization of two microsatellite polymorphisms at the AK155 locus, i.e. D12S2511 and D12S2510. The first is located in the third intron and the second in the 3' region of the gene. Both might be useful as markers in association or linkage studies of polygenic inflammatory or allergic diseases. No association with multiple sclerosis was found for each of these markers by means of the transmission disequilibrium test in an extended number of Sardinian simplex families.     

Genetic admixture in three mexican mestizo populations based on D1S80 and HLA‐DQA1 Loci

This study compares genetic polymorphisms at the D1S80 and HLA‐DQA1 loci in three Mexican Mestizo populations from three large states (Nuevo León, Jalisco, and the Federal District). Allele frequency distributions are relatively homogenous in the three samples; only the Federal District population shows minor differences of the HLA‐DQA1 allele frequencies compared with the other two. In terms of genetic composition, these Mestizo populations show evidence of admixture with predominantly Spanish‐European (50–60%) and Amerindian (37–49%) contributions; the African contribution (1–3%) is minor. Together with the observation that in Nuevo León, the admixture estimates based on D1S80 and HLA‐DQA1, are virtually the same as those reported earlier from blood group loci, suggests that DNA markers, such as D1S80 and HLA‐DQA1 are useful for examining genetic homogeneity/heterogeneity across Mestizo populations of Mexico. The inverse relationship of the proportion of gene diversity due to population differences (G_st) to within population gene diversity (H_s) is also consistent with theoretical predictions, supporting the use of these markers for population genetics studies. Am. J. Hum. Biol. 14:257–263, 2002. © 2002 Wiley‐Liss, Inc.     

Analysis of polymorphisms at the tumor suppressor gene p53 (TP53) in contributing to the risk for schizophrenia and its associated neurocognitive deficits

Owing to the role of the nuclear phosphoprotein p53 in the regulation of neurodegeneration and neurodevelopmental processes, some authors have suggested TP53 as a candidate gene for schizophrenia and/or the neurocognitive deficits commonly observed in these patients. In the present study we have analyzed two polymorphisms (Pro72Arg and 16 bp insertion) located on the TP53 gene in order to investigate their role in the risk of developing schizophrenia and their effect on the neurocognitive profile of these patients in the context of an association study. The distribution of genotypes, alleles and haplotypes did not differ between cases and controls. Additionally, we did not detect any influence of this genetic variability in the neurocognitive functions of schizophrenic patients. Our findings suggest that the analyzed variability of the TP53 gene does not influence (i) the risk of suffering from schizophrenia and (ii) the deficits in the neurocognitive profile of these patients.     

Genetic variability at the D1S80 minisatellite: predominance of allele 18 among some indian populations

BACKGROUND: Hypervariable minisatellites are considered as useful genetic markers in population studies because they are highly polymorphic, multiallelic and co-dominant in nature. The D1S80 minisatellite is one of the well studied markers, and has been used for differentiating population groups of various geographic, linguistic, cultural and genetic origins. OBJECTIVE: The present study reports the genetic variation observed at the D1S80 minisatellite among seven anthropologically distinct ethnic groups from Kerala state in south India and is compared with other reported Indian and world populations. SUBJECTS AND METHODS: DNA was isolated from the peripheral blood samples of 282 random, normal and healthy volunteers, PCR amplified and electrophoresed on 4% PAGE followed by silver staining. RESULTS: A total of 22 alleles (14-39 repeats) were detected with high heterozygosity (0.63-0.84) and Polymorphic Information Content (PIC) values (0.63-0.83). Allele 18 was the predominant allele, except in Ezhavas. The comparison of allele frequency data with world populations including other studied Indian ethnic groups has revealed that the majority of Indian populations possessed allele 18 as the predominant allele. In contrast, allele 24 was reported to be the predominant allele worldwide with a few exceptions. CONCLUSIONS: This study at the D1S80 minisatellite on seven ethnic groups will provide useful information for the Indian population genetic database. However, the most important observation was the predominance of allele 18 among the majority of Indian ethnic groups. The reason is not clear yet and thus further studies on Indian ethnic groups from different regions are necessary to find out the importance of allele 18 as the predominant allele in Indian population.     

Behavior of loci D1S1656 and D12S391 in a sample from Maracaibo,Venezuela

Two recently reported short tandem repeat polymorphisms characterized by PCR, D1S1656 and D12S391, were investigated in a sample from Maracaibo, an admixed population of Venezuela, in order to evaluate their application in forensic and population genetics studies. The unbiased heterozygosities were 0.9011 and 0.8444 for locus D1S1656 and D12S391, respectively. The joint discrimination power and joint probability of exclusion were 0.99972 and 0.93287. When allele frequencies of locus D1S1656 from Maracaibo were compared with eight other populations, our group clustered with the European or European‐derived samples, mainly from Spain. In the comparison of locus D12S391 with 16 populations, Maracaibo clustered with 3 Asian samples. The high heterozygosity and discrimination power make these two loci important candidates to be considered for STR packages for forensic and population genetic purposes. Am. J. Hum. Biol. 15:68–71, 2003. © 2002 Wiley‐Liss, Inc.