Are Ischemic Stroke and Alzheimer's Disease Genetically Consecutive Pathologies?

Complex diseases that affect the functioning of the central nervous system pose a major problem for modern society. Among these, ischemic stroke (IS) holds a special place as one of the most common causes of disability and mortality worldwide. Furthermore, Alzheimer's disease (AD) ranks first among neurodegenerative diseases, drastically reducing brain activity and overall life quality and duration. Recent studies have shown that AD and IS share several common risk and pathogenic factors, such as an overlapping genomic architecture and molecular signature. In this review, we will summarize the genomics and RNA biology studies of IS and AD, discussing the interconnected nature of these pathologies. Additionally, we highlight specific genomic points and RNA molecules that can serve as potential tools in predicting the risks of diseases and developing effective therapies in the future.

Evaluation of Density-Based Spatial Clustering for Identifying Genomic Loci Associated with Ischemic Stroke in Genome-Wide Data.

The genetic architecture of ischemic stroke (IS), which is one of the leading causes of death worldwide, is complex and underexplored. The traditional approach for associative gene mapping is genome-wide association studies (GWASs), testing individual single-nucleotide polymorphisms (SNPs) across the genomes of case and control groups. The purpose of this research is to develop an alternative approach in which groups of SNPs are examined rather than individual ones. We proposed, validated and applied to real data a new workflow consisting of three key stages: grouping SNPs in clusters, inferring the haplotypes in the clusters and testing haplotypes for the association with phenotype. To group SNPs, we applied the clustering algorithms DBSCAN and HDBSCAN to linkage disequilibrium (LD) matrices, representing pairwise r2 values between all genotyped SNPs. These clustering algorithms have never before been applied to genotype data as part of the workflow of associative studies. In total, 883,908 SNPs and insertion/deletion polymorphisms from people of European ancestry (4929 cases and 652 controls) were processed. The subsequent testing for frequencies of haplotypes restored in the clusters of SNPs revealed dozens of genes associated with IS and suggested the complex role that protocadherin molecules play in IS. The developed workflow was validated with the use of a simulated dataset of similar ancestry and the same sample sizes. The results of classic GWASs are also provided and discussed. The considered clustering algorithms can be applied to genotypic data to identify the genomic loci associated with different qualitative traits, using the workflow presented in this research.

The Study of the Association of Polymorphisms in LSP1, GPNMB, PDPN, TAGLN, TSPO, and TUBB6 Genes with the Risk and Outcome of Ischemic Stroke in the Russian Population.

To date, there has been great progress in understanding the genetic basis of ischemic stroke (IS); however, several aspects of the condition remain underexplored, including the influence of genetic factors on post-stroke outcomes and the identification of causative loci. We proposed that an analysis of the results obtained from animal models of brain ischemia could be helpful. To this end, we developed a bioinformatic approach for exploring single-nucleotide polymorphisms (SNPs) in human orthologs of rat genes expressed differentially after induced brain ischemia. Using this approach, we identified and analyzed 11 SNPs from 6 genes in 553 Russian individuals (331 patients with IS and 222 controls). We assessed the association of SNPs with the risk of IS and IS outcomes. We found that the SNPs rs858239 (GPNMB), rs907611 (LSP1), and rs494356 (TAGLN) were associated with different parameters of IS functional outcomes. In addition, the SNP rs1261025 (PDPN) was associated significantly with IS itself (p = 0.0188, recessive model). All these associations were demonstrated for the first time. Analysis of the literature suggests that they should be characterized as being inflammation related. This supports the pivotal role of inflammation in both the incidence of stroke and post-stroke outcomes. We believe the findings reported here will help with stroke prognosis in the future.

Analysis of Common SNPs across Continents Reveals Major Genomic Differences between Human Populations.

Common alleles tend to be more ancient than rare alleles. These common SNPs appeared thousands of years ago and reflect intricate human evolution including various adaptations, admixtures, and migration events. Eighty-four thousand abundant region-specific alleles (ARSAs) that are common in one continent but absent in the rest of the world have been characterized by processing 3100 genomes from 230 populations. Also computed were 17,446 polymorphic sites with regional absence of common alleles (RACAs), which are widespread globally but absent in one region. A majority of these region-specific SNPs were found in Africa. America has the second greatest number of ARSAs (3348) and is even ahead of Europe (1911). Surprisingly, East Asia has the highest number of RACAs (10,524) and the lowest number of ARSAs (362). ARSAs and RACAs have distinct compositions of ancestral versus derived alleles in different geographical regions, reflecting their unique evolution. Genes associated with ARSA and RACA SNPs were identified and their functions were analyzed. The core 100 genes shared by multiple populations and associated with region-specific natural selection were examined. The largest part of them (42%) are related to the nervous system. ARSA and RACA SNPs are important for both association and human evolution studies.

CAPN3 c.1746-20C>G variant is hypomorphic for LGMD R1 calpain 3-related.

The investigated intronic CAPN3 variant NM_000070.3:c.1746-20C>G occurs in the Central and Eastern Europe with a frequency of >1% and there are conflicting interpretations on its pathogenicity. We collected data on 14 patients carrying the CAPN3 c.1746-20C>G variant in trans position with another CAPN3 pathogenic/likely pathogenic variant. The patients compound heterozygous for the CAPN3 c.1746-20C>G variant presented a phenotype consistent with calpainopathy of mild/medium severity. This variant is most frequent in the North/West regions of Russia and may originate from that area. Molecular studies revealed that different splicing isoforms are produced in the muscle. We hypothesize that c.1746-20C>G is a hypomorphic variant with a reduction of RNA and protein expression and only individuals having a higher ratio of abnormal isoforms are affected. Reclassification of the CAPN3 variant c.1746-20C>G from variant with a conflicting interpretation of pathogenicity to hypomorphic variant explains many unidentified cases of limb girdle muscular dystrophy R1 calpain 3-related in Eastern and Central Europe.

Examination of Genetic Variants Revealed from a Rat Model of Brain Ischemia in Patients with Ischemic Stroke: A Pilot Study.

Although there has been great progress in understanding the genetic bases of ischemic stroke (IS), many of its aspects remain underexplored. These include the genetics of outcomes, as well as problems with the identification of real causative loci and their functional annotations. Therefore, analysis of the results obtained from animal models of brain ischemia could be helpful. We have developed a bioinformatic approach exploring single nucleotide polymorphisms (SNPs) in human orthologues of rat genes expressed differentially under conditions of induced brain ischemia. Using this approach, we identified and analyzed nine SNPs in 553 Russian individuals (331 patients with IS and 222 controls). We explored the association of SNPs with both IS outcomes and with the risk of IS. SNP rs66782529 (LGALS3) was associated with negative IS outcomes (p = 0.048). SNPs rs62278647 and rs2316710 (PTX3) were associated significantly with IS (p = 0.000029 and p = 0.0025, respectively). These correlations for rs62278647 and rs2316710 were found only in women, which suggests a sex-specific association of the PTX3 polymorphism. Thus, this research not only reveals some new genetic associations with IS and its outcomes but also shows how exploring variations in genes from a rat model of brain ischemia can be of use in searching for human genetic markers of this disorder.

A Workflow for Selection of Single Nucleotide Polymorphic Markers for Studying of Genetics of Ischemic Stroke Outcomes.

In this paper we propose a workflow for studying the genetic architecture of ischemic stroke outcomes. It develops further the candidate gene approach. The workflow is based on the animal model of brain ischemia, comparative genomics, human genomic variations, and algorithms of selection of tagging single nucleotide polymorphisms (tagSNPs) in genes which expression was changed after ischemic stroke. The workflow starts from a set of rat genes that changed their expression in response to brain ischemia and results in a set of tagSNPs, which represent other SNPs in the human genes analyzed and influenced on their expression as well.

Global Picture of Genetic Relatedness and the Evolution of Humankind.

We performed an exhaustive pairwise comparison of whole-genome sequences of 3120 individuals, representing 232 populations from all continents and seven prehistoric people including archaic and modern humans. In order to reveal an intricate picture of worldwide human genetic relatedness, 65 million very rare single nucleotide polymorphic (SNP) alleles have been bioinformatically processed. The number and size of shared identical-by-descent (IBD) genomic fragments for every pair of 3127 individuals have been revealed. Over 17 million shared IBD fragments have been described. Our approach allowed detection of very short IBD fragments (<20 kb) that trace common ancestors who lived up to 200,000 years ago. We detected nine distinct geographical regions within which individuals had strong genetic relatedness, but with negligible relatedness between the populations of these regions. The regions, comprising nine unique genetic components for mankind, are the following: East and West Africa, Northern Europe, Arctica, East Asia, Oceania, South Asia, Middle East, and South America. The level of admixture in every studied population has been apportioned among these nine genetic components. Genetically, long-term neighboring populations are strikingly similar to each other in spite of any political, religious, and cultural differences. The topmost admixture has been observed at the center of Eurasia. These admixed populations (including Uyghurs, Azerbaijanis, Uzbeks, and Iranians) have roughly equal genetic contributions from the Middle East, Europe, China, and India, with additional significant traces from Africa and Arctic. The entire picture of relatedness of all the studied populations unfolds and presents itself in the form of shared number/size of IBDs.

imputeqc: an R package for assessing imputation quality of genotypes and optimizing imputation parameters.

BACKGROUND: The imputation of genotypes increases the power of genome-wide association studies. However, the imputation quality should be assessed in each particular case. Nevertheless, not all imputation softwares control the error of output, e.g., the last release of fastPHASE program (1.4.8) lacks such an option. In this particular software there is also an uncertainty in choosing the model parameters. fastPHASE is based on haplotype clusters, which size should be set a priori. The parameter influences the results of imputation and downstream analysis. RESULTS: We present a software toolkit imputeqc to assess the imputation quality and/or to choose the model parameters for imputation. We demonstrate the efficacy of toolkit for evaluation of imputations made with both fastPHASE and BEAGLE software for HapMap and 1000 Genomes data. The discordance of genotypes received correlated well in both methods. Using imputeqc, we also shown how to choose the optimal number of haplotype clusters and expectation-maximization cycles for fastPHASE program. The found number of haplotype clusters of 25 was further applied for hapFLK testing that revealed signatures of selection at LCT region on chromosome 2. We also demonstrated how to decrease the computational time in the case of hapFLK testing from 3 days to 20 h. CONCLUSIONS: The toolkit is implemented as an R package imputeqc and command line scripts. The code is freely available at https://github.com/inzilico/imputeqc under the MIT license.

Genomic landscape of the signals of positive natural selection in populations of Northern Eurasia: A view from Northern Russia.

Natural selection of beneficial genetic variants played a critical role in human adaptation to a wide range of environmental conditions. Northern Eurasia, despite its severe climate, is home to lots of ethnically diverse populations. The genetic variants associated with the survival of these populations have hardly been analyzed. We searched for the genomic signatures of positive selection in (1) the genome-wide microarray data of 432 people from eight different northern Russian populations and (2) the whole-genome sequences of 250 people from Northern Eurasia from a public repository through testing the extended haplotype homozigosity (EHH) and direct comparison of allele frequency, respectively. The 20 loci with the strongest selection signals were characterized in detail. Among the top EHH hits were the NRG3 and NBEA genes, which are involved in the development and functioning of the neural system, the PTPRM gene, which mediates cell-cell interactions and adhesion, and a region on chromosome 4 (chr4:28.7-28.9 Mb) that contained several loci affiliated with different classes of non-coding RNAs (RN7SL101P, MIR4275, MESTP3, and LINC02364). NBEA and the region on chromosome 4 were novel selection targets that were identified for the first time in Western Siberian populations. Cross-population comparisons of EHH profiles suggested a particular role for the chr4:28.7-28.9 Mb region in the local adaptation of Western Siberians. The strongest selection signal identified in Siberian sequenced genomes was formed by six SNPs on chromosome 11 (chr11:124.9-125.2 Mb). This region included well-known genes SLC37A2 and PKNOX2. SLC37A2 is most-highly expressed in the gut. Its expression is regulated by vitamin D, which is often deficient in northern regions. The PKNOX2 gene is a transcription factor of the homeobox family that is expressed in the brain and many other tissues. This gene is associated with alcohol addiction, which is widespread in many Northern Eurasian populations.

Reconstructing genetic history of Siberian and Northeastern European populations.

Siberia and Northwestern Russia are home to over 40 culturally and linguistically diverse indigenous ethnic groups, yet genetic variation and histories of peoples from this region are largely uncharacterized. We present deep whole-genome sequencing data (∼38×) from 28 individuals belonging to 14 distinct indigenous populations from that region. We combined these data sets with additional 32 modern-day and 46 ancient human genomes to reconstruct genetic histories of several indigenous Northern Eurasian populations. We found that Siberian and East Asian populations shared 38% of their ancestry with a 45,000-yr-old Ust'-Ishim individual who was previously believed to have no modern-day descendants. Western Siberians trace 57% of their ancestry to ancient North Eurasians, represented by the 24,000-yr-old Siberian Mal'ta boy MA-1. Eastern Siberian populations formed a distinct sublineage that separated from other East Asian populations ∼10,000 yr ago. In addition, we uncovered admixtures between Siberians and Eastern European hunter-gatherers from Samara, Karelia, Hungary, and Sweden (from 8000-6600 yr ago); Yamnaya people (5300-4700 yr ago); and modern-day Northeastern Europeans. Our results provide new insights into genetic histories of Siberian and Northeastern European populations and evidence of ancient gene flow from Siberia into Europe.

GSTM1 copy number variation in the context of single nucleotide polymorphisms in the human GSTM cluster.

BACKGROUND: GSTM1 gene deletion is one of the most known copy number polymorphisms in human genome. It is most likely caused by homologous recombination between the repeats flanking the gene. However, taking into account that the deletion has no crucial effects on human well-being, and the ability of other GSTMs to compensate for the lack of GSTM1, a role for additional factors affecting GSTM1 deletion can be proposed. Our goal was to explore the relationships between GSTM1 deletion polymorphism and single nucleotide polymorphisms (SNPs) in the region of the GSTM cluster that includes GSTM2, GSTM3, GSTM4, and GSTM5 in addition to GSTM1. RESULTS: Real-time polymerase chain reaction was used to quantify the number of GSTM1 copies. Fourteen SNPs from the region were tested and their allelic patterns were compared in groups of Russian individuals subdivided according to their GSTM1 deletion genotypes. Linkage disequilibrium-based haplotype analysis showed substantial differences of haplotype frequencies between the groups, especially between individuals with homozygous GSTM1 -/- and +/+ genotypes. Exploration of the results of phasing of GSTM1 and SNP genotypes revealed unequal segregation of GSTM1 + and - alleles at different haplotypes. CONCLUSIONS: The observed differences in haplotype patterns suggest the potential role of genetic context in GSTM1 deletion frequency (appearance) and in the determination of the deletion-related effects.

Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women.

IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. DESIGN, SETTING, AND PARTICIPANTS: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. MAIN OUTCOMES AND MEASURES: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. RESULTS: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

A New Baltic Population-Specific Human Genetic Marker in the PMCA4 Gene.

OBJECTIVES: The PMCA gene family consists of 4 genes and at least 21 splice variants; among these, the Ca2+ ATPase 4 (PMCA4) gene encodes a plasma membrane protein abundantly expressed in several tissues, including the kidney, heart, and sperm. Knockout of PMCA4 causes infertility due to immotile sperm in mouse models. We therefore investigated variants in this gene for potential association with infertility in groups of Estonian (n = 191) and Latvian (n = 92) men with reduced sperm motility. METHODS: All exons, exon-intron boundaries, 5' and 3' untranslated regions, and the promoter region of the PMCA4 gene were analysed by direct sequencing for a group of Estonian infertile men. Genotyping of guanine and adenine alleles of rs147729934 was performed, using a custom-designed TaqMan® probe for a group of Latvian infertile men as well as additional groups from Latvia and several groups of people with proven ethnicity from the Baltic region. RESULTS: Although we did not identify any significant associations between variants in the gene and infertility, our results indicated that in all studied Latvian and Estonian groups the adenine allele of the variant rs147729934 was present at a higher frequency than expected. Analysis of additional samples indicated that the adenine allele of rs147729934 likely originated once in the modern-day Baltic or western Russia area, as the frequency of the minor adenine allele observed in this region is remarkably higher than that in the general European population. CONCLUSIONS: Our results revealed no significant difference in frequencies of genetic variants in PMCA4 gene between men with normal and those with reduced sperm motility. The adenine allele of the variant rs147729934 is potentially an informative tool for future population studies concerning ancient Baltic and Finno-Ugric history.

Pharmacogenomic assessment of cisplatin-based chemotherapy outcomes in ovarian cancer.

AIM: Cisplatin and its analogs are potent antitumor agents. However, their use is restricted by significant variability in tumor response and toxicity. There is a great need to identify genetic markers to predict the most important adverse events and patient outcomes. MATERIALS & METHODS: We have evaluated the association between polymorphisms in 106 genes involved mainly in xenobiotic metabolism, DNA repair, the cell cycle and apoptosis, and outcomes in 104 ovarian cancer patients receiving cisplatin-cyclophosphamide chemotherapy. Arrayed primer extension technology was used to genotype 228 SNPs. RESULTS: Ten SNPs in nine genes were found to be associated with one or more of the assessed clinical end points. SNPs in TPMT and NQO1 were significantly associated with progression-free survival. Polymorphisms in ERCC5, RAD52, MUTYH and LIG3 correlated with the occurrence of severe neutropenia. SNPs in NAT2 and EPHX1 were associated with anemia and nephrotoxicity, respectively. A SNP in ADH1C was correlated with complete tumor response. CONCLUSION: The results obtained suggest that SNPs in different genes involved in drug metabolism can be important in identifying patients at risk for nonresponse to or toxicity from cisplatin-based treatment.

A genome-wide analysis of populations from European Russia reveals a new pole of genetic diversity in northern Europe.

Several studies examined the fine-scale structure of human genetic variation in Europe. However, the European sets analyzed represent mainly northern, western, central, and southern Europe. Here, we report an analysis of approximately 166,000 single nucleotide polymorphisms in populations from eastern (northeastern) Europe: four Russian populations from European Russia, and three populations from the northernmost Finno-Ugric ethnicities (Veps and two contrast groups of Komi people). These were compared with several reference European samples, including Finns, Estonians, Latvians, Poles, Czechs, Germans, and Italians. The results obtained demonstrated genetic heterogeneity of populations living in the region studied. Russians from the central part of European Russia (Tver, Murom, and Kursk) exhibited similarities with populations from central-eastern Europe, and were distant from Russian sample from the northern Russia (Mezen district, Archangelsk region). Komi samples, especially Izhemski Komi, were significantly different from all other populations studied. These can be considered as a second pole of genetic diversity in northern Europe (in addition to the pole, occupied by Finns), as they had a distinct ancestry component. Russians from Mezen and the Finnic-speaking Veps were positioned between the two poles, but differed from each other in the proportions of Komi and Finnic ancestries. In general, our data provides a more complete genetic map of Europe accounting for the diversity in its most eastern (northeastern) populations.

Genetic characterization of northeastern Italian population isolates in the context of broader European genetic diversity.

Population genetic studies on European populations have highlighted Italy as one of genetically most diverse regions. This is possibly due to the country's complex demographic history and large variability in terrain throughout the territory. This is the reason why Italy is enriched for population isolates, Sardinia being the best-known example. As the population isolates have a great potential in disease-causing genetic variants identification, we aimed to genetically characterize a region from northeastern Italy, which is known for isolated communities. Total of 1310 samples, collected from six geographically isolated villages, were genotyped at >145000 single-nucleotide polymorphism positions. Newly genotyped data were analyzed jointly with the available genome-wide data sets of individuals of European descent, including several population isolates. Despite the linguistic differences and geographical isolation the village populations still show the greatest genetic similarity to other Italian samples. The genetic isolation and small effective population size of the village populations is manifested by higher levels of genomic homozygosity and elevated linkage disequilibrium. These estimates become even more striking when the detected substructure is taken into account. The observed level of genetic isolation in Friuli-Venezia Giulia region is more extreme according to several measures of isolation compared with Sardinians, French Basques and northern Finns, thus proving the status of an isolate.

Analysis of DNA variations in GSTA and GSTM gene clusters based on the results of genome-wide data from three Russian populations taken as an example.

BACKGROUND: Extensive genome-wide analyses of many human populations, using microarrays containing hundreds of thousands of single-nucleotide polymorphisms, have provided us with abundant information about global genomic diversity. However, these data can also be used to analyze local variability in individual genomic regions. In this study, we analyzed the variability in two genomic regions carrying the genes of the GSTA and GSTM subfamilies, located on different chromosomes. RESULTS: Analysis of the polymorphisms in GSTA and GSTM gene clusters showed similarities in their allelic and haplotype diversities. These patterns were similar in three Russian populations and the CEU population of European origin. There were statistically significant differences in all the haploblocks of both the GSTM and GSTA regions when the Russian populations were compared with populations from China and Japan. Most haploblocks also differed between the Russians and Nigerians from Yoruba, but, some of them had similar allelic frequencies. Special attention was paid to SNP rs4986947 from the intron of the GSTA4 gene, which is represented in apes by an A nucleotide. In the Asian and African samples, it was represented only by a G allele, and both allelic variants (G/A) occurred in the Russian and European populations. CONCLUSIONS: The results obtained suggest the presence of common features in the evolutionary histories of the GSTA and GSTM gene regions, and that African subpopulations were involved differently in the formation of the European and Asian human lineages.

Pharmacogenomics of cisplatin-based chemotherapy in ovarian cancer patients of different ethnic origins.

AIM: There is a substantial difference between Asians and Caucasians in their reaction to platinum drugs. To determine whether population-related genomics contribute to differences in patient outcomes, pharmacogenomic relevance of polymorphisms in some genes, the protein activities of which may affect aspects of cisplatin metabolism, were evaluated. PATIENTS & METHODS: Nineteen polymorphisms in ten genes were tested for correlations with the efficacy and toxicity of a cisplatin-cyclophosphamide regimen in Yakut and Russian patients with ovarian cancer. RESULTS: The CYP2E1 7632T>A polymorphism was associated with progression-free survival (p = 0.015) in Yakuts. In Russians, progression-free survival was correlated with the GSTP1 Ile105Val polymorphism (p = 0.004). Yakut patients with the GSTT1-null genotype had a higher risk for nephrotoxicity. By contrast, in the Russian group, nephrotoxicity was more frequent among patients with heterozygous ERCC1 genotypes. Severe emesis in Yakuts was independently associated with two polymorphisms in the CYP2E1 gene but in Russians, it was more common in patients with the GSTT1-null genotype. Differences in genotypic correlations with anemia were also observed. CONCLUSION: Significant differences in genotype distribution between Russian and Yakut women were observed for ten of the 19 polymorphisms, but none of them seemed to be a clear casual candidate and further studies involving more markers are required.

Specificity of genetic diversity in D1S80 revealed by SNP-VNTR haplotyping.

BACKGROUND: The allele frequency patterns of the D1S80 variable number tandem repeat (VNTR) locus have been shown to be multimodal in many different human populations. AIM: To explore the complex allele distribution of the D1S80 polymorphic locus in different populations comparing the derived single nucleotide polymorphism (SNP) rs16824398-D1S80 haplotype frequencies in samples of European (Russians), Asian (Yakuts) and sub-Saharan African origin. SUBJECTS AND METHODS: The D1S80 locus together with its 5'-flanking region including SNP rs16824398 was amplified using allele-specific polymerase chain reaction (PCR). RESULTS: Haplotype phase determination sub-divided the total D1S80 allele spectrum into two allele sets marked by the corresponding SNP rs16824398 alleles. In non-African samples, the most frequent D1S80 alleles had 24 and 18 repeats that were associated with different SNP backgrounds (T and G alleles, respectively). Both combinations also occurred in Africans, but these samples exhibited an expanded spectrum of VNTR alleles on both SNP backgrounds. CONCLUSIONS: The sub-division of the D1S80 allele spectrum shape on the linked SNP background is indicative of populations of the main human groups. The reported differences in D1S80 allele spectra between populations of different ethnic origins can be explained by the ratios of chromosomes with T and G alleles.