Association of the CTLA4 promoter region (-1661G allele) with type 1 diabetes in the South Moroccan population.

The contribution of the candidate gene CTLA4 to type 1 diabetes is not well established. Although several polymorphisms have been repeatedly associated to the disease, several studies have not confirmed the association. The joint analysis of three SNPs in the CTLA4 promoter region (-1722, -1661, and -319), one SNP in the first exon (+49), and one dinucleotide repeat in the 3' untranslated region, in a case-control study in a North African population, shows a strong association of the CTLA4 region with the disease. The -1661G allele showed a significant association with an odds ratio of 2.13. Moreover, the internal structure of the dinucleotide repeat has been deeply analyzed. The present results reveal the importance of polymorphisms in the CTLA4 promoter region, their probable role in gene expression and, ultimately, their relation to the etiology of type 1 diabetes. Previous contradictory association studies might be due to the effect of linkage disequilibrium between the polymorphism analyzed and the alteration within the CTLA4 region. This alteration may be different depending on the genetic background of the population. The present work stresses the need to perform exhaustive analysis of the promoter region polymorphisms in order to detect association with the disease.

Origins and divergence of the Roma (gypsies).

The identification of a growing number of novel Mendelian disorders and private mutations in the Roma (Gypsies) points to their unique genetic heritage. Linguistic evidence suggests that they are of diverse Indian origins. Their social structure within Europe resembles that of the jatis of India, where the endogamous group, often defined by profession, is the primary unit. Genetic studies have reported dramatic differences in the frequencies of mutations and neutral polymorphisms in different Romani populations. However, these studies have not resolved ambiguities regarding the origins and relatedness of Romani populations. In this study, we examine the genetic structure of 14 well-defined Romani populations. Y-chromosome and mtDNA markers of different mutability were analyzed in a total of 275 individuals. Asian Y-chromosome haplogroup VI-68, defined by a mutation at the M82 locus, was present in all 14 populations and accounted for 44.8% of Romani Y chromosomes. Asian mtDNA-haplogroup M was also identified in all Romani populations and accounted for 26.5% of female lineages in the sample. Limited diversity within these two haplogroups, measured by the variation at eight short-tandem-repeat loci for the Y chromosome, and sequencing of the HVS1 for the mtDNA are consistent with a small group of founders splitting from a single ethnic population in the Indian subcontinent. Principal-components analysis and analysis of molecular variance indicate that genetic structure in extant endogamous Romani populations has been shaped by genetic drift and differential admixture and correlates with the migrational history of the Roma in Europe. By contrast, social organization and professional group divisions appear to be the product of a more recent restitution of the caste system of India.

Allele frequencies of 13 short tandem repeats in population samples from the Iberian Peninsula and northern Africa.

The 13 short tandem repeat (STR) loci D3S1358, vWA, FGA, D16S539, TH01, TPOX, CSF1PO, D8S1179, D21S11, D18S51, D5S818, D13S317 and D7S820 as well as the amelogenin locus, contained in AmpFlSTR Profiler Plus and/or AmpFlSTR Cofiler and/or AmpFlSTR Green I PCR amplification kits, were studied in four populations from the Iberian Peninsula, Basques, Catalans, Andalusians and Portuguese and two North African populations (Moroccan Arabs and Berbers). The aim of the study was to obtain accurate allele frequency data and other genetic parameters of forensic interest on the main representative human groups living in Iberia and Morocco using an automated method and commercial amplification kits.

Genetic structure of north-west Africa revealed by STR analysis.

We have analysed a large set of autosomal short tandem repeat (STR) loci in several Arabic and Berber-speaking groups from north-west Africa (ie Moroccan Arabs, northern-central and southern Moroccan Berbers, Saharawis, and Mozabites). Two levels of analysis have been devised using two sets of 12STR loci, (D3S1358, vWA, FGA, THO1, TPOX, CSF1PO, D8S1179, D21S11, D18S51, D5S818, D13S317 and D7S820) and 21 (the former set plus D9S926, D11S2010, D13S767, D14S306, D18S848, D2S1328, D4S243, F13A1, and FES/FPS). For each set, data for a number of external reference populations were gathered from the literature. Several methods of analysis based on genetic distances (neighbour-joining trees, principal coordinate analysis, boundary detection), as well as AMOVA, showed that genetic differentiation among NW African populations was very low and devoid of any spatial pattern. When the NW African populations were grouped according to cultural or linguistic differences, the partition was not associated with genetic differentiation. Thus, it is likely that Arabisation was mainly a cultural process. A clear genetic difference was found between NW African populations and Iberians, which underscores the Gilbraltar Straits as a strong barrier to genetic exchange; nonetheless, some degree of gene flow into Southern Iberia may have existed. NW Africans were genetically closer to Iberians and to other Europeans than to African Americans.

Y chromosome STR haplotypes in four populations from northwest Africa.

The eight short tandem repeat (STR) polymorphic systems mapping on the male-specific region of the human Y chromosome, DYS19, DYS388, DYS389I, DYS389II, DYS390, DYS391, DYS392 and DYS393, were typed in four populations from northwest (NW) Africa (Moroccan Arabs, southern Moroccan Berbers, Saharawis and Mozabites). Allele frequency distributions showed statistically significant differences for all loci among all the populations except for DYS19. Complete typing was obtained for 185 chromosomes, which showed 74 different haplotypes. The two most frequent haplotypes were found in 16.2% and 15.1% of the individuals, although the latter was almost exclusively found in the Mozabites. Locus and haplotype informativeness were measured by means of the gene diversity (D). The haplotype diversity ranged from 0.856 (Mozabites) to 0.967 (southern Moroccan Berbers). For some loci, allele frequencies in NW Africans were clearly different from those in Europeans. The most common NW African haplotype was found only in one individual out of a total of 494 Europeans typed for the whole STR set. Thus, NW African and European Y chromosomes are clearly differentiated.

Population growth of human Y chromosomes: a study of Y chromosome microsatellites.

We use variation at a set of eight human Y chromosome microsatellite loci to investigate the demographic history of the Y chromosome. Instead of assuming a population of constant size, as in most of the previous work on the Y chromosome, we consider a model which permits a period of recent population growth. We show that for most of the populations in our sample this model fits the data far better than a model with no growth. We estimate the demographic parameters of this model for each population and also the time to the most recent common ancestor. Since there is some uncertainty about the details of the microsatellite mutation process, we consider several plausible mutation schemes and estimate the variance in mutation size simultaneously with the demographic parameters of interest. Our finding of a recent common ancestor (probably in the last 120,000 years), coupled with a strong signal of demographic expansion in all populations, suggests either a recent human expansion from a small ancestral population, or natural selection acting on the Y chromosome.

Variation in short tandem repeats is deeply structured by genetic background on the human Y chromosome.

Eleven biallelic polymorphisms and seven short-tandem-repeat (STR) loci mapping on the nonrecombining portion of the human Y chromosome have been typed in men from northwestern Africa. Analysis of the biallelic markers, which represent probable unique events in human evolution, allowed us to characterize the stable backgrounds or haplogroups of Y chromosomes that prevail in this geographic region. Variation in the more rapidly mutating genetic markers (STRs) has been used both to estimate the time to the most recent common ancestor for STR variability within these stable backgrounds and to explore whether STR differentiation among haplogroups still retains information about their phylogeny. When analysis of molecular variance was used to study the apportionment of STR variation among both genetic backgrounds (i.e., those defined by haplogroups) and population backgrounds, we found STR variability to be clearly structured by haplogroups. More than 80% of the genetic variance was found among haplogroups, whereas only 3.72% of the genetic variation could be attributed to differences among populations-that is, genetic variability appears to be much more structured by lineage than by population. This was confirmed when two population samples from the Iberian Peninsula were added to the analysis. The deep structure of the genetic variation in old genealogical units (haplogroups) challenges a population-based perspective in the comprehension of human genome diversity. A population may be better understood as an association of lineages from a deep and population-independent gene genealogy, rather than as a complete evolutionary unit.

A founder mutation in the GK1 gene is responsible for galactokinase deficiency in Roma (Gypsies).

Galactokinase deficiency is an inborn error in the first step of galactose metabolism. Its major clinical manifestation is the development of cataracts in the first weeks of life. It has also been suggested that carriers of the deficiency are predisposed to presenile cataracts developing at age 20-50 years. Newborn screening data suggest that the gene frequency is very low worldwide but is higher among the Roma in Europe. Since the cloning of the galactokinase gene (GK1) in 1995, only two disease-causing mutations, both confined to single families, have been identified. Here we present the results of a study of six affected Romani families from Bulgaria, where index patients with galactokinase deficiency have been detected by the mass screening. Genetic linkage mapping placed the disease locus on 17q, and haplotype analysis revealed a small conserved region of homozygosity. Using radiation hybrid mapping, we have shown that GK1 is located in this region. The founder Romani mutation identified in this study is a single nucleotide substitution in GK1 resulting in the replacement of the conserved proline residue at amino acid position 28 with threonine (P28T). The P28T carrier rate in this endogamous population is approximately 5%, suggesting that the mutation may be an important cause of early childhood blindness in countries with a sizeable Roma minority.

Recent male-mediated gene flow over a linguistic barrier in Iberia, suggested by analysis of a Y-chromosomal DNA polymorphism.

We have examined the worldwide distribution of a Y-chromosomal base-substitution polymorphism, the T/C transition at SRY-2627, where the T allele defines haplogroup 22; sequencing of primate homologues shows that the ancestral state cannot be determined unambiguously but is probably the C allele. Of 1,191 human Y chromosomes analyzed, 33 belong to haplogroup 22. Twenty-nine come from Iberia, and the highest frequencies are in Basques (11%; n=117) and Catalans (22%; n=32). Microsatellite and minisatellite (MSY1) diversity analysis shows that non-Iberian haplogroup-22 chromosomes are not significantly different from Iberian ones. The simplest interpretation of these data is that haplogroup 22 arose in Iberia and that non-Iberian cases reflect Iberian emigrants. Several different methods were used to date the origin of the polymorphism: microsatellite data gave ages of 1,650, 2,700, 3,100, or 3,450 years, and MSY1 gave ages of 1,000, 2,300, or 2,650 years, although 95% confidence intervals on all of these figures are wide. The age of the split between Basque and Catalan haplogroup-22 chromosomes was calculated as only 20% of the age of the lineage as a whole. This study thus provides evidence for direct or indirect gene flow over the substantial linguistic barrier between the Indo-European and non-Indo-European-speaking populations of the Catalans and the Basques, during the past few thousand years.

Sex-specific migration patterns in Central Asian populations, revealed by analysis of Y-chromosome short tandem repeats and mtDNA.

Eight Y-linked short-tandem-repeat polymorphisms (DYS19, DYS388, DYS389I, DYS389II, DYS390, DYS391, DYS392, and DYS393) were analyzed in four populations of Central Asia, comprising two lowland samples-Uighurs and lowland Kirghiz-and two highland samples-namely, the Kazakhs (altitude 2,500 m above sea level) and highland Kirghiz (altitude 3,200 m above sea level). The results were compared with mtDNA sequence data on the same individuals, to study possible differences in male versus female genetic-variation patterns in these Central Asian populations. Analysis of molecular variance (AMOVA) showed a very high degree of genetic differentiation among the populations tested, in discordance with the results obtained with mtDNA sequences, which showed high homogeneity. Moreover, a dramatic reduction of the haplotype genetic diversity was observed in the villages at high altitude, especially in the highland Kirghiz, when compared with the villages at low altitude, which suggests a male founder effect in the settlement of high-altitude lands. Nonetheless, mtDNA genetic diversity in these highland populations is equivalent to that in the lowland populations. The present results suggest a very different migration pattern in males versus females, in an extended historical frame, with a higher migration rate for females.

Microsatellites provide evidence for Y chromosome diversity among the founders of the New World.

Recently, Y chromosome markers have begun to be used to study Native American origins. Available data have been interpreted as indicating that the colonizers of the New World carried a single founder haplotype. However, these early studies have been based on a few, mostly complex polymorphisms of insufficient resolution to determine whether observed diversity stems from admixture or diversity among the colonizers. Because the interpretation of Y chromosomal variation in the New World depends on founding diversity, it is important to develop marker systems with finer resolution. Here we evaluate the hypothesis of a single-founder Y haplotype for Amerinds by using 11 Y-specific markers in five Colombian Amerind populations. Two of these markers (DYS271, DYS287) are reliable indicators of admixture and detected three non-Amerind chromosomes in our sample. Two other markers (DYS199, M19) are single-nucleotide polymorphisms mostly restricted to Native Americans. The relatedness of chromosomes defined by these two markers was evaluated by constructing haplotypes with seven microsatellite loci (DYS388 to 394). The microsatellite backgrounds found on the two haplogroups defined by marker DYS199 demonstrate the existence of at least two Amerind founder haplotypes, one of them (carrying allele DYS199 T) largely restricted to Native Americans. The estimated age and distribution of these haplogroups places them among the founders of the New World.

Trading genes along the silk road: mtDNA sequences and the origin of central Asian populations.

Central Asia is a vast region at the crossroads of different habitats, cultures, and trade routes. Little is known about the genetics and the history of the population of this region. We present the analysis of mtDNA control-region sequences in samples of the Kazakh, the Uighurs, the lowland Kirghiz, and the highland Kirghiz, which we have used to address both the population history of the region and the possible selective pressures that high altitude has on mtDNA genes. Central Asian mtDNA sequences present features intermediate between European and eastern Asian sequences, in several parameters-such as the frequencies of certain nucleotides, the levels of nucleotide diversity, mean pairwise differences, and genetic distances. Several hypotheses could explain the intermediate position of central Asia between Europe and eastern Asia, but the most plausible would involve extensive levels of admixture between Europeans and eastern Asians in central Asia, possibly enhanced during the Silk Road trade and clearly after the eastern and western Eurasian human groups had diverged. Lowland and highland Kirghiz mtDNA sequences are very similar, and the analysis of molecular variance has revealed that the fraction of mitochondrial genetic variance due to altitude is not significantly different from zero. Thus, it seems unlikely that altitude has exerted a major selective pressure on mitochondrial genes in central Asian populations.

HLA evidence for the lack of genetic heterogeneity in Basques.

To examine the possible internal heterogeneity within the Basque population, nine samples typed for several HLA loci were compiled and HLA-A, B, C and DR loci were analysed. First, the shared features of HLA in Basques were analysed by principal component analysis and genetic distances. Two major Basque dialect groups ('French' and 'Spanish') were considered. FST statistics were computed and corrected for sampling intensity. The dialectal and political division did not seem to differentiate these two groups genetically. Analysis of Molecular Variance also failed to show consistently significant genetic variance components between French and Spanish Basques. Thus, in this particular example, linguistic diversity does not seem to correlate with a genetic stratification.

HLA class I and class II DNA typing and the origin of Basques.

Seven HLA class I and class II loci (HLA-A, B, C, DRB1, DQA1, DPA1 and DPB1) were typed at the DNA level in two populations of the Iberian Peninsula (100 Basque and 88 Catalan individuals) in order to unravel their genetic relationship and to compare these results with other European and Mediterranean populations. For the first time, the frequencies of alleles and haplotypes for the class I HLA loci at the DNA level in these populations are presented. The most frequent haplotype in both populations is A*29-Cw*1601-B*44-DRB1*0701-DQA1*0201-DPA1*0103-DPB 1*0401. Neither population differed markedly from the highly homogeneous European and Mediterranean genetic landscape. The Basques, a European outlier population according to classical genetic markers, appear to lie within the genetic European variation with a slight uniqueness and show no clear relationship to North African populations, as has been postulated in some previous HLA studies. Here, the range of possibilities provided by the highly polymorphic HLA system is stressed by using genetic distances, phylogenetic trees and principal component analyses in order to reconstruct population history.

Population genetics of Y-chromosome short tandem repeats in humans.

Eight human short tandem repeat polymorphisms (STRs) also known as microsatellites-DYS19, DYS388, DYS390, DYS391, DYS392, DYS393, DYS389I, and DYS389II, mapping in the Y chromosome-were analyzed in two Iberian samples (Basques and Catalans). Allele frequency distributions showed significant differences only for DYS392. Fst and gene diversity index (D) were estimated for the Y STRs. The values obtained are comparable to those of autosomal STR if corrections for the smaller effective population size on the Y chromosome are taken into account. This suggests that Y-chromosome microsatellites might be as useful as their autosomal counterparts to both human population genetics and forensics. Our results also reinforce the hypothesis that selective sweeps in the Y chromosome in recent times are unlikely. Haplotypes combining five of the loci were constructed for 71 individuals, showing 29 different haplotypes. A haplotype tree was constructed, from which an estimate of 7,000 to 60,000 years for the age of the Y-chromosome variation in Iberia was derived, in accordance with previous estimates obtained with mtDNA sequences and nuclear markers.

Allele frequencies for 20 microsatellites in a worldwide population survey.

20 microsatellite polymorphisms: HUMHPRT, HUMD3S1358, HUMTH01, HUMACPP, HUMVWF, HUMD16S310, HUMD4S243, HUMTPO, HUMFES/FPS, HUMF13A1, HUMDHFRP2, HUMD11S2010, HUMD13S767, HUMD9S926, HUMD2S1328, HUMD14S306, HUMD18S848, HUMD5S818, HUMD7S820 and HUMFGA were analyzed in a worldwide survey covering five continents and allele frequencies are given. There is a high heterogeneity in allele frequencies among continents. A neighbor-joining tree based on Fst distance shows a pattern of differentiation that may reflect the role of drift in the development of genetic differences among humans. The variation found between continents confirms the usefulness of tetranucleotide microsatellites in human genetic variation studies.

Population history of north Africa: evidence from classical genetic markers.

After an intensive bibliographic search, we compiled all the available data on allele frequencies for classical genetic polymorphisms referring to North African populations and synthesized the data in an attempt to reconstruct the populations' demographic history using two complementary methods: (1) principal components analysis and (2) genetic distances represented by neighbor-joining trees. In both analyses the main feature of the genetic landscape in northern Africa is an east-west pattern of variation pointing to the differentiation between the Berber and Arab population groups of the northwest and the populations of Libya and Egypt. Moreover, Libya and Egypt show the smallest genetic distances with the European populations, including the Iberian Peninsula. The most plausible interpretation of these results is that, although demic diffusion during the Neolithic could explain the genetic similarity between northeast Africa and Europe by a parallel process of gene flow from the Near East, a Mesolithic (or older) differentiation of the populations in the northwestern regions with later limited gene flow is needed to understand the genetic picture. The most isolated groups (Mauritanians, Tuaregs, and south Algerian Berbers) were the most differentiated and, although no clear structure can be discerned among the different Arab- and Berber-speaking groups, Arab speakers as a whole are closer to Egyptians and Libyans. By contrast, the genetic contribution of sub-Saharan Africa appears to be small.

PIP: An extensive bibliographic search was conducted to compile all available data on allele frequencies for classical genetic polymorphisms referring to North African populations. The data were then synthesized to reconstruct the population's demographic history using principal components analysis and genetic distances represented by neighbor-joining trees. Both analyses identified an east-west pattern of genetic variation in northern Africa pointing to the differentiation between the Berber and Arab population groups of the northwest and the populations of Libya and Egypt. Libya and Egypt are also the smallest genetic distances away from European populations. Demic diffusion during the Neolithic period could explain the genetic similarity between northeast Africa and Europe through a parallel process of gene flow from the Near East, but a Mesolithic or older differentiation of the populations into the northwestern regions with later limited gene flow is needed to understand this genetic picture. Mauritanians, Tuaregs, and south Algerian Berbers, the most isolated groups, were the most differentiated, while Arab speakers overall are closer to Egyptians and Libyans. The genetic contribution of sub-Saharan Africa appears to be small.

Mitochondrial DNA variation and the origin of the Europeans.

Sequences from the mitochondrial DNA (mtDNA) control region were analyzed in nine European and West Asian populations. They showed low genetic heterogeneity when compared to world populations. However, a Caucasoid population tree displayed a robust east-west gradient. Within-population diversity (ascertained through various parameters) and mean pairwise differences declined from east to west, in a pattern compatible with ancient population migration and expansion from the Middle East. Estimated expansion times indicate a Paleolithic event with important differences among populations according to their geographical position and thus a slower tempo than previously believed. The replacement of Neanderthals by anatomically modern humans, fully compatible with the present results, may have been a slower and more complex process than cultural change suggests.

Evaluation of Y-chromosomal STRs: a multicenter study.

A multicenter study has been carried out to characterize 13 polymorphic short tandem repeat (STR) systems located on the male specific part of the human Y chromosome (DYS19, DYS288, DYS385, DYS388, DYS389I/II, DYS390, DYS391, DYS392, DYS393, YCAI, YCAII, YCAIII, DXYS156Y). Amplification parameters and electrophoresis protocols including multiplex approaches were compiled. The typing of non-recombining Y loci with uniparental inheritance requires special attention to population substructuring due to prevalent male lineages. To assess the extent of these subheterogeneities up to 3825 unrelated males were typed in up to 48 population samples for the respective loci. A consistent repeat based nomenclature for most of the loci has been introduced. Moreover we have estimated the average mutation rate for DYS19 in 626 confirmed fatherson pairs as 3.2 x 10(-3) (95% confidence interval limits of 0.00041-0.00677), a value which can also be expected for other Y-STR loci with similar repeat structure. Recommendations are given for the forensic application of a basic set of 7 STRs (DYS19, DYS3891, DYS389II, DYS390, DYS391, DYS392, DYS393) for standard Y-haplotyping in forensic and paternity casework. We recommend further the inclusion of the highly polymorphic bilocal Y-STRs DYS385, YCAII, YCAIII for a nearly complete individualisation of almost any given unrelated male individual. Together, these results suggest that Y-STR loci are useful markers to identify males and male lineages in forensic practice.