Genetic structure of the Kuwaiti population revealed by paternal lineages.

OBJECTIVE: We analyzed the Y-chromosome haplogroup diversity in the Kuwaiti population to gain a more complete overview of its genetic landscape. METHOD: A sample of 117 males from the Kuwaiti population was studied through the analysis of 22 Y-SNPs. The results were then interpreted in conjunction with those of other populations from the Middle East, South Asia, North and East Africa, and East Europe. RESULTS: The analyzed markers allowed the discrimination of 19 different haplogroups with a diversity of 0.7713. J-M304 was the most frequent haplogroup in the Kuwaiti population (55.5%) followed by E-M96 (18%). They revealed a genetic homogeneity between the Kuwaiti population and those of the Middle East (FST = 6.1%, P-value < 0.0001), although a significant correlation between genetic and geographic distances was found (r = 0.41, P-value = 0.009). Moreover, the nonsignificant pairwise FST genetic distances between the Kuwait population on the one hand and the Arabs of Iran and those of Sudan on the other, corroborate the hypothesis of bidirectional gene flow between Arabia and both Iran and Sudan. CONCLUSION: Overall, we have revealed that the Kuwaiti population has experienced significant gene flow from neighboring populations like Saudi Arabia, Iran, and East Africa. Therefore, we have confirmed that the population of Kuwait is genetically coextensive with those of the Middle East.

Mosaic maternal ancestry in the Great Lakes region of East Africa.

The Great Lakes lie within a region of East Africa with very high human genetic diversity, home of many ethno-linguistic groups usually assumed to be the product of a small number of major dispersals. However, our knowledge of these dispersals relies primarily on the inferences of historical, linguistics and oral traditions, with attempts to match up the archaeological evidence where possible. This is an obvious area to which archaeogenetics can contribute, yet Uganda, at the heart of these developments, has not been studied for mitochondrial DNA (mtDNA) variation. Here, we compare mtDNA lineages at this putative genetic crossroads across 409 representatives of the major language groups: Bantu speakers and Eastern and Western Nilotic speakers. We show that Uganda harbours one of the highest mtDNA diversities within and between linguistic groups, with the various groups significantly differentiated from each other. Despite an inferred linguistic origin in South Sudan, the data from the two Nilotic-speaking groups point to a much more complex history, involving not only possible dispersals from Sudan and the Horn but also large-scale assimilation of autochthonous lineages within East Africa and even Uganda itself. The Eastern Nilotic group also carries signals characteristic of West-Central Africa, primarily due to Bantu influence, whereas a much stronger signal in the Western Nilotic group suggests direct West-Central African ancestry. Bantu speakers share lineages with both Nilotic groups, and also harbour East African lineages not found in Western Nilotic speakers, likely due to assimilating indigenous populations since arriving in the region ~3000 years ago.

Paternal lineages in Libya inferred from Y-chromosome haplogroups.

Many studies based on genetic diversity of North African populations have contributed to elucidate the modelling of the genetic landscape in this region. North Africa is considered as a distinct spatial-temporal entity on geographic, archaeological, and historical grounds, which has undergone the influence of different human migrations along its shaping. For instance, Libya, a North African country, was first inhabited by Berbers and then colonized by a variety of ethnic groups like Phoenicians, Greeks, Romans, Arabs and, in recent times, Italians. In this study, we contribute to clarify the genetic variation of Libya and consequently, of North African modern populations, by the study of Libyan male lineages. A total of 22 Y-chromosome-specific SNPs were genotyped in a sample of 175 Libyan males, allowing the characterization of 18 Y-chromosomal haplogroups. The obtained data revealed a predominant Northwest African component represented by haplogroup E-M81 (33.7%) followed by J(xJ1a,J2)-M304 (27.4%), which is postulated to have a Middle Eastern origin. The comparative study with other populations (∼5,400 individuals from North Africa, Middle East, Sub-Saharan Africa, and Europe) revealed a general genetic homogeneity among North African populations (FST = 5.3 %; P-value < 0.0001). Overall, the Y-haplogroup diversity in Libya and in North Africa is characterized by two genetic components. The first signature is typical of Berber-speaking people (E-M81), the autochthonous inhabitants, whereas the second is (J(xJ1a,J2)-M304), originating from Arabic populations. This is in agreement with the hypothesis of an Arabic expansion from the Middle East, shaping the North African genetic landscape.

The multiethnic ancestry of Bolivians as revealed by the analysis of Y-chromosome markers.

We have analyzed the specific male genetic component of 226 Bolivians recruited in five different regions ("departments"), La Paz, Cochabamba, Pando, Beni, and Santa Cruz. To evaluate the effect of geography on the distribution of genetic variability, the samples were also grouped into three main eco-geographical regions, namely, Andean, Sub-Andean, and Llanos. All the individuals were genotyped for 17 Y-STR and 32 Y-SNP markers. The average Y-chromosome Native American component in Bolivians is 28%, and it is mainly represented by haplogroup Q1a3a, while the average Y-chromosome European ancestry is 65%, and it is mainly represented by haplogroup R1b1-P25. The data indicate that there exists significant population sub-division in the country in terms of continental ancestry. Thus, the partition of ancestries in Llanos, Sub-Andean, and Andean regions is as follows (respectively): (i) Native American ancestry: 47%, 7%, and 19%, (ii) European ancestry: 46%, 86%, and 75%, and (iii) African ancestry: 7%, 7%, and 6%. The population sub-structure in the country is also well mirrored when inferred from an AMOVA analysis, indicating that among-population variance in the country reaches 9.74-11.15%. This suggests the convenience of using regional datasets for forensic applications in Bolivia, instead of using a global and single country database. By comparing the Y-chromosome patterns with those previously reported on the same individuals on autosomal SNPs and mitochondrial DNA (mtDNA), it becomes clear that Bolivians show a strong gender-bias.

Population genetics of 17 Y-STR markers in West Libya (Tripoli region).

Seventeen Y-chromosomal Short Tandem Repeats (Y-STR) included in the AmpFlSTR Y-filer PCR Amplification kit (Applied Biosystems) (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635 and GATA H4) were genotyped in a population sample of 176 unrelated males from western Libya (Tripoli region). A total of 142 different haplotypes were found, 124 being unique. Haplotype diversity was 0.9950. Both R(ST) pairwise analyses and multidimensional scaling plot show a close genetic relationship between Tripoli and North African populations.

The genetic landscape of Equatorial Guinea and the origin and migration routes of the Y chromosome haplogroup R-V88.

Human Y chromosomes belonging to the haplogroup R1b1-P25, although very common in Europe, are usually rare in Africa. However, recently published studies have reported high frequencies of this haplogroup in the central-western region of the African continent and proposed that this represents a 'back-to-Africa' migration during prehistoric times. To obtain a deeper insight into the history of these lineages, we characterised the paternal genetic background of a population in Equatorial Guinea, a Central-West African country located near the region in which the highest frequencies of the R1b1 haplogroup in Africa have been found to date. In our sample, the large majority (78.6%) of the sequences belong to subclades in haplogroup E, which are the most frequent in Bantu groups. However, the frequency of the R1b1 haplogroup in our sample (17.0%) was higher than that previously observed for the majority of the African continent. Of these R1b1 samples, nine are defined by the V88 marker, which was recently discovered in Africa. As high microsatellite variance was found inside this haplogroup in Central-West Africa and a decrease in this variance was observed towards Northeast Africa, our findings do not support the previously hypothesised movement of Chadic-speaking people from the North across the Sahara as the explanation for these R1b1 lineages in Central-West Africa. The present findings are also compatible with an origin of the V88-derived allele in the Central-West Africa, and its presence in North Africa may be better explained as the result of a migration from the south during the mid-Holocene.

The peopling of Europe and the cautionary tale of Y chromosome lineage R-M269.

Recently, the debate on the origins of the major European Y chromosome haplogroup R1b1b2-M269 has reignited, and opinion has moved away from Palaeolithic origins to the notion of a younger Neolithic spread of these chromosomes from the Near East. Here, we address this debate by investigating frequency patterns and diversity in the largest collection of R1b1b2-M269 chromosomes yet assembled. Our analysis reveals no geographical trends in diversity, in contradiction to expectation under the Neolithic hypothesis, and suggests an alternative explanation for the apparent cline in diversity recently described. We further investigate the young, STR-based time to the most recent common ancestor estimates proposed so far for R-M269-related lineages and find evidence for an appreciable effect of microsatellite choice on age estimates. As a consequence, the existing data and tools are insufficient to make credible estimates for the age of this haplogroup, and conclusions about the timing of its origin and dispersal should be viewed with a large degree of caution.

Capillary electrophoresis of an X-chromosome STR decaplex for kinship deficiency cases.

During the two last decades, STR markers located on the autosomes have been gaining relevance and have nearly replaced the use of other type of markers in most cases of genetic identification, paternity testing, as well as in other situations of kinship analysis. Nevertheless, in some complex cases, independently of the number of polymorphisms being typed, autosomal markers convey very little information. Depending on the parentage constellation available for analysis, as well as the gender of the subjects, this problem can sometimes be solved by using markers that have different modes of transmission. Therefore, most forensic laboratories are nowadays prepared to analyse lineage markers (Y chromosome and mtDNA) and many have recently set up methods for the analysis of X-STRs. In the present chapter, a method is described for the typing of ten X chromosome-specific markers in a single PCR amplification reaction, followed by capillary electrophoresis separation and fluorescent detection in an ABI Genetic Analyser apparatus. This typing strategy was developed and optimized for the simultaneous amplification of ten X-linked specific STRs well distributed along the chromosome: DXS8378, DXS9902, DXS7132, DXS9898, DXS6809, DXS6789, DXS7133, GATA172D05, GATA31E08 and DXS7423.

Influence of CYP2C9 genetic variants on gastrointestinal bleeding associated with nonsteroidal anti-inflammatory drugs: a systematic critical review.

The existence of genetic polymorphisms in metabolizing enzymes can be regarded as one of the principal causes of interindividual variation in response to drugs and adverse reactions. In the case of enzyme CYP2C9, the presence of genetic coding variants could be considered a risk factor for suffering from gastrointestinal haemorrhages associated with the use of nonsteroidal anti-inflammatory drugs, due to a reduction in the enzyme's rate of metabolism. The aim of this study was to conduct a systematic critical review aimed at assessing whether the presence of CYP2C9*2 and CYP2C9*3 could increase the risk of suffering from gastrointestinal haemorrhages due to nonsteroidal anti-inflammatory drug use. Using MEDLINE as the data source, the search was limited to scientific studies published in English. Six studies met the inclusion criteria, whereas three reported no results because there were no homozygous mutant genotypes for CYP2C9*2 and *3 in their samples, risk of bleeding was associated by one with the presence of CYP2C9*2 and by two with the CYP2C9*3 coding variant. Some of the studies included in this review contained methodological limitations, which prevented the increased risk of suffering gastrointestinal haemorrhages due to nonsteroidal anti-inflammatory drug use from being satisfactorily linked to the presence of CYP2C9 coding variants.

Signatures of the preagricultural peopling processes in sub-Saharan Africa as revealed by the phylogeography of early Y chromosome lineages.

The study of Y chromosome variation has helped reconstruct demographic events associated with the spread of languages, agriculture, and pastoralism in sub-Saharan Africa, but little attention has been given to the early history of the continent. In order to overcome this lack of knowledge, we carried out a phylogeographic analysis of haplogroups A and B in a broad data set of sub-Saharan populations. These two lineages are particularly suitable for this objective because they are the two most deeply rooted branches of the Y chromosome genealogy. Their distribution is almost exclusively restricted to sub-Saharan Africa where their frequency peaks at 65% in groups of foragers. The combined high-resolution single nucleotide polymorphism analysis with short tandem repeats variation of their subclades reveals strong geographic and population structure for both haplogroups. This has allowed us to identify specific lineages related to regional preagricultural dynamics in different areas of sub-Saharan Africa. In addition, we observed signatures of relatively recent contact, both among Pygmies and between them and Khoisan speaker groups from southern Africa, thus contributing to the understanding of the complex evolutionary relationships among African hunter-gatherers. Finally, by revising the phylogeography of the very early human Y chromosome lineages, we have obtained support for the role of southern Africa as a sink, rather than a source, of the first migrations of modern humans from eastern and central parts of the continent. These results open new perspectives on the early history of Homo sapiens in Africa, with particular attention to areas of the continent where human fossil remains and archaeological data are scant.

Genetic profile characterization of 10 X-STRs in four populations of the southeastern region of Brazil.

Ten X-chromosomal short tandem repeats (DXS8378, DXS9902, DXS7132, DXS9898, DXS6809, DXS6789, DXS7133, GATA172D05, GATA31E08 and DXS7423) were analyzed in four populations of the southeastern region of Brazil (São Paulo, Rio de Janeiro, Vitória and Belo Horizonte). No deviations from the Hardy-Weinberg equilibrium were observed for any of the analyzed loci in the four populations. The average diversity per locus varied between 68% for DXS8378, DXS7133, and DXS7423 and 83%, for DXS6809, with Rio de Janeiro being the most diverse population. Overall power of discrimination values in females varied between 0.99999999990 and 0.99999999997 and between 0.9999991 and 0.9999995 in males. These high values show the potential of this system for forensic application and relationships' testing in the studied groups. Genetic comparisons (exact tests of population differentiation and pairwise genetic distances) revealed significant differences between Brazilian and other populations from Europe, Latin America and Africa, as well as among different Brazilian populations.

Nilotes from Karamoja, Uganda: haplotype data defined by 17 Y-chromosome STRs.

In this work 118 Nilote male samples were genotyped from Karamoja region, in Northeast Uganda, through 17 Y-chromosomal short tandem repeats (STRs)-DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635 and GATA H4.1. A total of 94 different haplotypes were found, where 19 were shared by at least two individuals, and haplotype diversity amounted to 0.9958+/-0.0017. When considering only the nine Y-STRs included in the minimal haplotype (YHRD) the haplotype diversity decreased to 0.9807+/-0.0048, a similar value to those found in other African populations such as Mozambique, Angola and Guinea-Bissau. Population comparisons were performed between our sample and nine other African populations. Significant R(st) genetic distances were obtained between the Nilote population from Karamoja and all African populations used for comparison, except Xhosa sample from South Africa. In the multidimensional scaling (MDS) plot, the Karamoja sample is well separated from all other populations, standing between the Ethiopia and the Bantu samples, although closer to this last group.

An X-chromosome pentaplex in two linkage groups: haplotype data in Alagoas and Rio de Janeiro populations from Brazil.

Genotype data were obtained for five X-Chr STRs (DXS10079, DXS10074, DXS10075, DXS7424 and DXS101) in two different populations from Brazil, namely Alagoas and Rio de Janeiro. Observed genotype distributions in female samples for each locus do not show deviations from Hardy-Weinberg equilibrium expectations. Gametic association was tested for all pairs of loci in male samples. Significant association values were found between all pairs including DXS10079, DXS10074 and DXS10075, as well as between DXS7424 and DXS101, proving that these two groups of markers must be treated as haplotypes. No significant association could be found between markers from the two groups (DXS10079, DXS10074 or DXS10075 vs. DXS7424 or DXS101), although distances between them varied from 24 to 25cM. When comparing haplotype frequencies in Alagoas, Rio de Janeiro, Germany and Ghana, significant differences were found between the Brazilian and the Germany sample and that from Ghana. Nevertheless, no significant differences were found between Alagoas and Rio de Janeiro, as well as between these two populations and Germany. The combined power of discrimination in males and females were high in both Brazilian populations (>or=0.9996 and >or=0.9999998, respectively), showing the utility of these markers for human identification and paternity testing.

A new approach to long QT syndrome mutation detection by Sequenom MassARRAY system.

Congenital long QT syndrome is an inherited cardiac disorder characterized by a prolonged QT interval and polymorphic ventricular arrhythmias that could result in recurrent syncope, seizures or sudden death as the most dramatic event. Until now QT interval mutations have been described in 12 genes, where the majority of mutations reside in three genes KCNQ1, KCNH2, and SCN5A. Diagnosis and prognosis are directly related with the gene and mutation involved. We have developed a diagnostic approach for long QT syndrome and Brugada syndrome based on published mutations and Sequenom MassArray system. Three diagnostic tests have been developed, oriented to each of the three most prevalent genes in the long QT syndrome. A total of 433 mutations are analyzed in 38 multiplex reactions, allowing their detection in about 48 h. Tests were validated on 502 samples from individuals with different clinical conditions and family history. The average call rates obtained for each of the tests were 93, 83, and 73% in KCNQ1, KCNH2, and SCNA, respectively. Sequenom MassARRAY mutation detection is a reliable, highly flexible, and cost-efficient alternative to conventional methods for genetic testing in long QT syndrome and Brugada syndrome, facilitating flexible upgrades of the version of the test presented here with the inclusion of new mutations.

Digging deeper into East African human Y chromosome lineages.

The most significant and widely studied remodeling of the African genetic landscape is the Bantu expansion, which led to an almost total replacement of the previous populations from the sub-Saharan region. However, a poor knowledge exists about other population movements, namely, the Nilotic migration, which is a pastoralist dispersal that, contrary to the Bantu expansion, impacted only East African populations. Here, samples from a Ugandan Nilotic-speaking population were studied for 37 Y chromosome-specific SNPs, and the obtained data were compared with those already available for other sub-Saharan population groups. Although Uganda lies on the fringe of both Bantu and Nilotic expansions, a low admixture with Bantu populations was detected, with haplogroups carrying M13, M182 and M75 mutations prevailing in Nilotes together with a low frequency of the main Bantu haplogroups from clade E1b1a-M2. The results of a comparative analysis with data from other population groups allowed a deeper characterization of some lineages in our sample, clarifying some doubts about the origin of some particular Y-SNPs in different ethnic groups, such as M150, M112 and M75. Moreover, it was also possible to identify a new Y-SNP apparently specific to Nilotic groups, as well as the presence of particular haplogroups that characterize Nilotic populations. The detection of a new haplogroup B2a1b defined by G1, could be, therefore, important to differentiate Nilotes from other groups, helping to trace migration and admixture events that occurred in eastern Africa.

Population data on 15 autosomal STRs in a sample from Colombia.

We present population genetic data of 15 STRs (CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, PENTA D, PENTA E, TH01, TPOX and VWA) obtained from a sample of 617 unrelated individuals from Colombia. Deviations from Hardy-Weinberg equilibrium were assessed and allele frequencies and parameters of forensic interest for each STR were calculated. The combined power of exclusion (PE) and the combined power of discrimination (PD) for the 15 tested STR loci were 0, 99999895 and more than 0, 9999999, respectively. The combined MP value was 1 in 1, 07888 x 10(-17). Population comparisons between our sample and neighbouring populations from Latin America were carried out. Significant differences in above six markers were observed between our sample and two populations from Rio de Janeiro.

Prevalence of CYP2C9 polymorphisms in the south of Europe.

CYP2C9 is a major liver enzyme responsible of the metabolism of many clinically important drugs. The presence of CYP2C9 genetic polymorphisms has been associated with marked interindividual variability in its catalytic activity that could result in drug toxicity. Here we present frequencies of the most common CYP2C9 coding variants CYP2C9*2 (C430T) and CYP2C9*3 (A1075C) in representative samples of four regions from Spain (Basque Country, n=358; Catalonia, n=240; Central Spain, n=190 and Galicia, n=288) and one northern Italian region, (Verona, n=164), which range between 0.125 and 0.165 in the case of CYP2C9*2 and between 0.071 and 0.085 for CYP2C9*3. No significant differences between CYP2C9 allele frequencies were found comparing all the sampled populations. A more extensive comparative analysis using allele frequency data of populations widely spread over Europe was performed, showing significant differences in the CYP2C9*2 allele frequencies distribution between some of the regions, being quite homogeneous in the case of CYP2C9*3 variant. The results obtained show that above 40% of our samples carry a mutate allele, which can result in a poor metabolization of low therapeutic index drugs as oral anticoagulants (warfarin, acenocoumarol), oral antidiabetic drugs and some non-steroidal anti-inflammatory drugs. Our study constitutes both a large (n=1240) and robust allele frequency database on CYP2C9 polymorphisms, which represents one of the most numerous CYP2C9*2 and *3 database existing to date.

Population data defined by 15 autosomal STR loci in Karamoja population (Uganda) using AmpF/STR Identifiler kit.

Karamoja is a region located in the northeast edge of Uganda where it borders Kenya and Sudan. The majority of inhabitants of this region belong to Karimojong ethnic groups. In this work, we present allele frequencies for 15 STRs included in the AmpF/STR Identifiler kit (CSF1PO, D2S1338, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D19S433, D21S11, FGA, TH01, TPO and VWA) in 218 unrelated individuals from Karamoja region. Observed genotype distributions for each locus do not show deviations from Hardy-Weinberg equilibrium expectations. When comparing allele frequencies, for each locus, with other five African samples (Equatorial Guinea, Mozambique, Cabinda (Angola), Rwanda and Tanzania) the only population that did not show significant differences with Karamoja (Uganda) was Rwanda.

A GEP-ISFG collaborative study on the optimization of an X-STR decaplex: data on 15 Iberian and Latin American populations.

In a collaborative work carried out by the Spanish and Portuguese ISFG Working Group (GEP-ISFG), a polymerase chain reaction multiplex was optimized in order to type ten X-chromosome short tandem repeats (STRs) in a single reaction, including: DXS8378, DXS9902, DXS7132, DXS9898, DXS6809, DXS6789, DXS7133, GATA172D05, GATA31E08, and DXS7423. Using this X-decaplex, each 17 of the participating laboratories typed a population sample of approximately 200 unrelated individuals (100 males and 100 females). In this work, we report the allele frequencies for the ten X-STRs in 15 samples from Argentina (Buenos Aires, Córdoba, Río Negro, Entre Ríos, and Misiones), Brazil (São Paulo, Rio de Janeiro, Paraná, and Mato Grosso do Sul), Colombia (Antioquia), Costa Rica, Portugal (Northern and Central regions), and Spain (Galicia and Cantabria). Gene diversities were calculated for the ten markers in each population and all values were above 56%. The average diversity per locus varied between 66%, for DXS7133, and 82%, for DXS6809. For this set of STRs, a high discrimination power was obtained in all populations, both in males (> or =1 in 5 x 10(5)) and females (> or =1 in 3 x 10(9)), as well as high mean exclusion chance in father/daughter duos (> or =99.953%) and in father/mother/daughter trios (> or =99.999%). Genetic distance analysis showed no significant differences between northern and central Portugal or between the two Spanish samples from Galicia and Cantabria. Inside Brazil, significant differences were found between Rio de Janeiro and the other three populations, as well as between São Paulo and Paraná. For the five Argentinean samples, significant distances were only observed when comparing Misiones with Entre Ríos and with Río Negro, the only two samples that do not differ significantly from Costa Rica. Antioquia differed from all other samples, except the one from Río Negro.