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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.

Mitochondrial DNA sequences from Georgians and Kurds were analyzed in order to test the possible correlation between female lineages and languages in these two neighboring West Eurasian groups. Mitochondrial sequence pools in both populations are very similar despite their different linguistic and prehistoric backgrounds. Both populations present mtDNA lineages that clearly belong to the European gene pool, as shown by 1) similar nucleotide and sequence diversities; 2) a large number of sequences shared with the rest of European samples; 3) nonsignificant genetic distances; and 4) classification of the present lineages into the major European mtDNA haplogroups already described. The outlier position of the populations from the Caucasus according to classical genetic markers is not recognized in the present Georgian mtDNA sequence pool. This result suggests that the differentiation of mtDNA sequences in West Eurasia and the outlier features of Caucasian populations should be attributed to different processes. Moreover, the putative linguistic relationship between Caucasian groups and the Basques, another outlier population within Europe for classical genetic markers, is not detected by the analysis of mtDNA sequences., (Copyright 2000 Wiley-Liss, Inc.)

The distribution of the number of loci out of the 13 in the CODIS STR set that would show an exclusion (i.e., a genotype set incompatible either with the prosecution hypothesis or with Mendelian transmission) was estimated in different scenarios. The knowledge of this distribution would provide a framework against which casework evidence can be compared. I used allele frequencies in Iberian and in Italian populations to generate individual genotypes at random and to test in 1 million simulation replicates, how many of the 13 loci would give an exclusion in an individual identification case, a paternity case, and a double parenthood case. All three scenarios were tested under an expected overall exclusion, both for unrelated individuals and for cases in which the suspect or the alleged father was the brother of the real culprit or real father. Paternity and double parenthood cases were also tested in the true scenario, with exclusionary loci due to mutation. In individual identification cases, the average number of exclusionary loci was 11.95 with a minimum of 7. This STR set also showed sufficient power to resolve identification cases in which the evidence sample came from a suspect's sib. False paternity cases yielded an average of 7.65 exclusionary loci and exclusions with only one (0.0108%) or two (0.14%) exclusionary loci were obtained only rarely. The cases of exclusion with one locus could lead to likelihood ratios in favour of paternity, while both true and false paternity cases with two exclusionary loci would often lead to non-conclusive likelihood ratios. The average number of exclusionary loci in a paternity case where the alleged father was the real father's brother was 3.82, with a significant number of cases where no exclusions were obtained.

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.

Patterns of dystrophin gene deletions in DMD/BMD patients were compared in four populations: Turks (n = 146 deletions), Europeans (n = 838), North Indians (n = 89), and Indians from all over India (n = 103). Statistical tests revealed that there are differences in the proportions of small deletions. In contrast, the distribution of deletion breakpoints and the frequencies of specific deletions commonly observed in the four populations are not significantly different. The variations strongly suggest that sequence differences exist in the introns, and the differences are in agreement with genetic distances among populations. The similarities suggest that some intronic sequences have been conserved and that those will trigger recurrent deletions, since it is unlikely that gene flow would disperse the deleted chromosomes, which vanish from the gene pool in a few generations.

Genetic diversity in Europe has been interpreted as a reflection of phenomena occurring during the Paleolithic ( approximately 45,000 years before the present [BP]), Mesolithic ( approximately 18,000 years BP), and Neolithic ( approximately 10,000 years BP) periods. A crucial role of the Neolithic demographic transition is supported by the analysis of most nuclear loci, but the interpretation of mtDNA evidence is controversial. More than 2,600 sequences of the first hypervariable mitochondrial control region were analyzed for geographic patterns in samples from Europe, the Near East, and the Caucasus. Two autocorrelation statistics were used, one based on allele-frequency differences between samples and the other based on both sequence and frequency differences between alleles. In the global analysis, limited geographic patterning was observed, which could largely be attributed to a marked difference between the Saami and all other populations. The distribution of the zones of highest mitochondrial variation (genetic boundaries) confirmed that the Saami are sharply differentiated from an otherwise rather homogeneous set of European samples. However, an area of significant clinal variation was identified around the Mediterranean Sea (and not in the north), even though the differences between northern and southern populations were insignificant. Both a Paleolithic expansion and the Neolithic demic diffusion of farmers could have determined a longitudinal cline of mtDNA diversity. However, additional phenomena must be considered in both models, to account both for the north-south differences and for the greater geographic scope of clinical patterns at nuclear loci. Conversely, two predicted consequences of models of Mesolithic reexpansion from glacial refugia were not observed in the present study.

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.

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.

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.

We have reconstructed partial genealogies in a sample of 44 SW Amazonian Rondonian Surui, in which 45 dinucleotide short tandem repeat polymorphisms had previously been typed. The genotypes of 488 pairs of individuals having an age difference of 13 or greater were compared, and parentage was excluded if a pair failed to share an allele at more than one locus. In order to test the power of this method, we computed the expected distribution of the number of exclusionary loci for such pairs of unrelated individuals, as well as that for individuals with different degrees of relatedness, and compared it to the observed distribution. We estimated that the pairs compared contained approximately 20% of individual pairs with a first-cousin relation or closer. A total of 25 pairs were identified as possible parent-child. In three instances, we could identify two or more children having a common parent; we computed a relatedness coefficient in order to establish whether the children were full or half sibs. The genealogies inferred show that instances of polygyny and polyandry (or, alternatively, serial mating), in addition to apparent monogamy, can be found among the Surui. The Surui sample can be used as a model for paleoanthropological populations, in which the determination of relatedness can provide further insights into the social structure of past populations. We estimate that, depending on the history of the populations and the degree of inbreeding, 10-20 highly informative nuclear loci should be typed in order to infer genealogies with acceptable confidence.

A dinucleotide CA repeat within intron 1 of the CFTR gene has recently been identified. We have determined the allele frequencies of this polymorphism in samples from 18 populations covering all major geographical areas, with a total of 1,816 chromosomes. When considering allele distributions, African populations presented a wider range of alleles than other populations and also presented higher expected heterozygosities. Analysis of molecular variance showed that 8.04% of the genetic variance in this locus could be attributed to differences among populations. We concluded that the polymorphism in the CA repeat in intron 1 of the CFTR gene is highly informative in populations from all geographical regions of the world. Thus, it can be applied to family studies of unknown mutations causing cystic fibrosis (CF) and can provide valuable information for genetic counseling. Moreover, its analysis should be included in the haplotypic analysis of known CF mutations.

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.

Haplotypes consisting of the (CTG)n repeat, as well as several flanking markers at the myotonic dystrophy (DM) locus, were analyzed in normal individuals from 25 human populations (5 African, 2 Middle Eastern, 3 European, 6 East Asian, 3 Pacific/Australo-Melanesian, and 6 Amerindian) and in five nonhuman primate species. Non-African populations have a subset of the haplotype diversity present in Africa, as well as a shared pattern of allelic association. (CTG)18-35 alleles (large normal) were observed only in northeastern African and non-African populations and exhibit strong linkage disequilibrium with three markers flanking the (CTG)n repeat. The pattern of haplotype diversity and linkage disequilibrium observed supports a recent African-origin model of modern human evolution and suggests that the original mutation event that gave rise to DM-causing alleles arose in a population ancestral to non-Africans prior to migration of modern humans out of Africa.

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.

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.

Forty-five dinucleotide short tandem repeat polymorphisms were typed in ten large samples of a globally distributed set of populations. Although these markers had been selected for high heterozygosity in European populations, we found them to be sufficiently informative for linkage analysis in non-Europeans. Heterozygosity, mean number of alleles, and mean number of private alleles followed a common trend: they were highest in the African samples, were somewhat lower in Europeans and East Asians, and were lowest in Amerindians. Genetic distances also reflected this pattern, and distances modelled after the stepwise mutation model yielded trees that were less in agreement with other genetic and archaeological evidence than distances based on differentiation by drift (FST). Genetic variation in non-Africans seems to be a subset of that in Africans, supporting the replacement hypothesis for the origin of modern humans.

The hypervariable segment I of the control region of the mtDNA was sequenced in 45 unrelated individuals from Bioko and 50 from São Tomé, two islands in the Gulf of Guinea that have had very different settlement patterns: Bioko was colonized around 10000 BP, while São Tomé was first settled by the Portuguese, who brought African slaves to the island. Two different patterns of sequence variation are evident and are also clearly a consequence of their very different demographic histories. The Bubi present a low genetic diversity and it is likely that the island was colonized by a small number of individuals with small later migration. São Tomeans might be considered a subset of a mainland African population relocated to the island. They present high genetic diversity with a high number of sequences being shared with many continental populations. This study, with knowledge of the population history in island populations, strengthens the genetic approach to unravel past demographic events.

Earlier analysis of the Italian population showed patterns of genetic differentiation that were interpreted as being the result of population settlements going back to pre-Roman times. DNA disease mutations may be a powerful tool in further testing this hypothesis since the analysis of diseased individuals can detect variants too rare to be resolved in normal individuals. We present data on the relative frequencies of 60 cystic fibrosis (CF) mutations in Italy and the geographical distribution of the 12 most frequent CF mutations screened in 3492 CF chromosomes originating in 13 Italian regions. The 12 most frequent mutations characterize about 73% of the Italian CF chromosomes. The most common mutation, delta F508, has an average frequency of 51%, followed by N1303K and G542X, both with average frequencies around 5%. Multivariate analyses show that the relative frequencies of CF mutations are heterogeneous among Italian regions, and that this heterogeneity is weakly correlated with the geographical pattern of non-DNA 'classical' genetic markers. The northern regions are well differentiated from the central-southern regions and within the former group the western and eastern regions are remarkably distinct. Moreover, Sardinia shows the presence of mutation T338I, which seems absent in any other European CF chromosome. The north-western regions of Italy, characterized by the mutation 1717-1G-->A, were under Celtic influence, while the north-east regions, characterized by the mutations R1162X, 2183AA-->G and 711 + 5G-->A, were under the influence of the Venetic culture.

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.

Dopamine beta-hydroxylase (E.C. 1.14.17.1; protein abbreviation: DbetaH) catalyzes conversion of dopamine to norepinephrine. Previous work identified two expressed alleles of the gene encoding DbetaH (locus symbol DBH), containing either G or T at nucleotide position 910, resulting in specification by codon 304 of alanine (DBH*304A) or serine (DBH*304S), respectively. The current study employed denaturing gradient gel electrophoresis to identify these alleles, and after developing a PCR RFLP for rapid genotyping, estimated the frequencies of the alleles in African-Americans, European-Americans, and in several geographically dispersed populations (Mbuti, Danes, Adygei, Chinese, Japanese, Surui, Maya, and Nasioi). DBH*304A was the most common allele in all populations tested, with allele frequencies greater than 0.80 in each case. There was significant heterogeneity in allele frequency across population groups. The DBH*304S allele was most common in subjects of African descent, and least common in East Asians and individuals from indigenous populations of North and South America. The frequency of DBH*304S was significantly higher in African-Americans (0.16) than in European-Americans (0.06; P < 0.004). Of the four DBH*304S homozygotes observed, all were Europeans and three of the four were Danes. Based on empirical P-values generated by computer simulation, the observed proportions of DBH*304S homozygotes did not differ significantly from Hardy-Weinberg expectations in any of the populations after Bonferroni correction for multiple comparisons. The observation of significant heterogeneity in DBH*304S allele frequency across different population samples demonstrates the importance of controlling for population stratification in future studies testing for associations between DBH*304S and clinical phenotypes.

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.

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.

We present data on the population genetics of cystic fibrosis (CF) in Bulgaria, obtained by comprehensive mutation analysis and the construction of intragenic microsatellite haplotypes. The sample of 262 CF alleles analysed is representative of the patients diagnosed during the period of referral and of the three main ethnic groups in the country. deltaF508 accounted for 100% of Gypsy CF alleles, which thus differed significantly from both Bulgarians and ethnic Turks. In Bulgarian and Turkish CF patients, 92% of the mutant alleles were identified, yielding a total of 25 different mutations, of which only 7 occurred at frequencies higher than 1%. The findings were compared to other European populations and to the distribution of phenylketonuria mutations. Genetic distances and population trees demonstrated that in the south-eastern tip of Europe, the overall distribution of CF mutations and polymorphic haplotypes is very close to that of Mediterranean populations, with a high frequency of N1303K and G542X, a large number of rare mutations and a prevalence of the 23 31 13 haplotype in association with deltaF508. These findings are consistent with a main role for the Neolithic expansion in the shaping of the CF mutation spectrum in Bulgaria and southern Europe.

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.

A well defined Italian sample from Trino Vercellese (Northern Italy) is analysed for 75 nuclear DNA RFLPs. It represents the only European sample [Matullo et al 1994] which is unmixed in a comparative study of eight populations from four continents [Bowcock et al 1991a; Lin et al 1994]. Genetic substructure of this sample has been investigated by allele sharing distances and no bias or higher homogeneity is shown. Genetic variability between populations was measured by the FST statistics (average FST was 0.138 +/- 0.086). Average heterozygosity for eight populations was 0.312 +/- 0.069. Genetic distances were evaluated between pairs of populations. Phylogenetic trees were reconstructed and principal component analysis performed. Particular attention has been given to the genetic relationship between our sample and the mixed-Caucasoid sample: 14 out of 75 markers show statistically significant frequency differences (P < 0.05), 5 of which are significant at a probability level < 1%: GH/Bg1II (Lower system), D7S1/HindIII, D17S71/MspI, EPB3/PstI, HLA-DQA. Hypotheses on admixed origin of Europeans has been discussed.

This study presents an analysis of 20 tetranucleotide microsatellites in 16 worldwide human populations representing the major geographic groups. Global Fst values for the 20 microsatellites are indicators of their relative validity as tools in human population genetics. Four different measures of genetic distance (Fst, DSW, delta mu 2 and Rst) have been tested and compared with each other. Neighbor-joining trees have been constructed for all the measures of genetic distance and populations. Measures of genetic distance such as Fst, which does not consider different mutational relationships among alleles and has a known relationship to differentiation by drift, and to some extent DSW, reflect what is known of human evolution, while mutation-based distances such as Rst and delta mu 2 give very different results from those recognized from other sources (genetic or archaeological). When the genetic relationship between human populations is analyzed through allelic frequencies for microsatellites, the choice of distance may be a key issue in the picture obtained of genetic relationships between human populations. The results of the present study suggest that genetic drift played the main role in generating the present distributions of microsatellite alleles and their variation among human populations; the role of mutation must have been less important owing to the time constraint imposed by the small timescale in which most human differentiation has occurred. Moreover, the results support the theory of a recent origin of modern humans, although the existence of strong bottlenecks in the origin of the various human groups seems unlikely.

Using the Problem 2A data sets of GAW10, we assessed the power of four ascertainment schemes to localize major genes underlying a disease trait; the schemes were based on disease or quantitative trait status of nuclear families. MAPMAKER/SIBS was used to perform sib-pair analysis for all four data sets using marker data from three chromosomes, 4, 5 and 8. Each scheme varied in power to identify major genes underlying the quantitative traits depending on the genetic architecture of the data set. Three different methods, Haseman-Elston quantitative trait locus (QTL) regression analysis, maximum likelihood variance estimation and a non-parametric method, were used to assess the strength of linkage in all four data sets. False positive mappings localizing to the same region of the genome, verifiable across all three methods did not occur. Two major genes, MG1 and MG2, were successfully assigned to chromosomes 5 and 8, respectively, by at least one of the ascertainment schemes. MG1 was localized under two schemes, selection of families with exactly two affected sibs and selection of families with two sibs who had extremely discordant values for Q1. Additional weak evidence of the location of MG1 was also obtained under the other two ascertainment schemes. MG2 could not be detected by analyzing data sets ascertained either by affected sib pairs or by sib pairs with extremely discordant values for Q1. In the data set ascertained by a third strategy, selection of families with sib pairs extremely discordant for Q2, MG2 could be mapped to chromosome 8. A random ascertainment scheme yielded a data set in which we could find weak evidence for MG1 and no evidence for MG2. Thus our ability to detect major genes underlying the QTL depended on several factors which included the ascertainment scheme, the population allele frequencies, linkage and epistasis.

Segment I of the control region of mtDNA (360 bases) was sequenced in seven samples, each of 10 individuals inhabiting villages in the eastern Italian Alps (South Tyrol and Trentino). Three linguistic groups, German, Italian, and Ladin, were represented by two samples each; the seventh sample comes from an isolated group of German origin, the Mocheni, who are linguistically distinct and geographically separated from the bulk of the German speakers. Seventy-four polymorphic sites were identified, defining 63 different haplotypes. Mocheni and Ladin speakers tend to form two clusters in the evolutionary trees inferred from sequences. Analysis of molecular variance shows significant differentiation within samples, among them, and among linguistic groups. Genetic differences between the Ladins and the other groups are not much smaller than between Europeans and some Africans; variation is large within groups, as well, with the exception of only the Mocheni. In the evolutionary trees where the four alpine groups are compared with other European populations, Mocheni and especially Ladins appear as clear outliers. Romansch-speaking Swiss, who are linguistically related to Ladins, are not genetically similar to them, for this segment of DNA. Because the time elapsed since colonization of the Alps (< or = 12,000 years) is short in mutational terms, the only model accounting for the observed relationships between mtDNA variation and linguistic identity seems one in which a population ancestral to Ladin speakers was already differentiated long before the Alps were settled and the current linguistic affiliations were established. For the Mocheni, the results are consistent with a simpler episode of allele loss, from an original genetic pool common to the ancestors of the current German speakers.

Founder effect and linkage disequilibrium have been successfully exploited to map single gene disorders, and the study of isolated populations is emerging as a major approach to the investigation of genetically complex diseases. In the search for genetic isolates ranging from Pacific islands to Middle East deserts, the 10 million Gypsies resident in Europe have largely escaped the attention of geneticists. Because of their geographical ubiquity, lack of written history and the presumed social and cultural nature of their isolation, Gypsies are construed as not meeting the criteria for a well defined founder population. Gypsy society has a complex structure with subdivisions and stratifications that are incomprehensible to the surrounding populations. Marginalization by the health care systems in most countries results in a lack of information on causes of morbidity and mortality and little is known about hereditary disorders or the population genetic characteristics of Gypsies. This study is the first example of mapping a disease gene in endogamous Gypsy groups. Using lod score analysis and linkage disequilibrium, we have located a novel demyelinating neuropathy to a narrow interval on chromosome 8q24. We show that the disease, occurring in Gypsy groups of different identity and history of migrations, is caused by a single mutation whose origin predates the divergence of these groups.

The hypervariable segment I of the control region of the mtDNA (positions 16024-16383) was amplified from hair roots by PCR and sequenced in 45 unrelated individuals from Anatolia (Asian Turkey). Forty different sequences were found, defined by 56 variable positions, of which only one involves a transversion. The neighbor-joining tree of Kimura's distance matrix for all sequences shows four main clusters. Cluster D was found to be the most statistically robust of the four, and all the sequences in it shared a mutation that is present only in European and West Asian populations. The variability in cluster D could have originated between 37,000 and 107,000 years ago. No branch is unexpectedly long, denoting the absence of sequences that diverged much before the others. The pairwise difference distribution is bell-shaped, in accordance with a population expansion occurring roughly 35,000 to 100,000 years ago. When compared to other Caucasoid populations through the pairwise difference distribution, there is a pattern from the Middle East (older expansion) to the various European populations, with Turkey in an intermediate position; when Turkish sequences are compared through a neighbor-joining tree on a genetic distance matrix of populations, this position is again evidenced. Although there is a very low level of genetic divergence among Caucasoid populations as shown by mtDNA control region sequences, a geographic pattern of genetic variation emerges, denoting a stepping-stone position of Turkey between the Middle East and Europe, which is in agreement with the hypothesis of a replacement of Neanderthals by modern humans, which could be related to the Upper Paleolithic cultural expansion.

The control region of mitochondrial DNA has been widely studied in various human populations. This paper reports sequence data for hypervariable segments 1 and 2 of the control region from a population from southern Tuscany (Italy). The results confirm the high variability of the control region, with 43 different haplotypes in 49 individuals sampled. The comparison of this set of data with other European populations allows the reconstruction of the population history of Tuscany. Independent approaches, such as the estimation of haplotype diversity, mean pairwise differences, genetic distances and discriminant analysis, place the Tuscan sample in an intermediate position between sequences from culturally or geographically isolated regions of Europe (Sardinia, the Basque Country, Britain) and those from the Middle East. In spite of the remarkable genetic homogeneity in Europe, a degree of variability is shown by local European populations and homogeneity increases with the relative isolation of the population. The pattern of mitochondrial variation in Tuscany indicates the persistence of an ancient European component subsequently enriched by migrational waves, possibly from the Middle East.

The geographical distribution of 49 mtDNA sequences from 22 localities in Southern Tuscany, Italy, was studied by molecular analysis of variance, by a new spatial autocorrelation statistic specifically designed for sequence data and by reconstructing genealogies of haplotypes. All these methods indicated a high homogeneity of populations. Nevertheless, genetic variability showed significant departure from equilibrium expectations, in agreement with the predicted effects of a population expansion. We suggest that a past population expansion that was probably associated with a migrational wave and with local gene flow between localities prevented spatial structuring in Southern Tuscany.

Genetic and linguistic differentiations within Corsica were analysed and compared; the genetic relationships of Corsica to other Mediterranean populations were also studied. Lexical distances between 49 Corsican localities were computed from a standard word list; trees built from these distances were compared with average linkage and neighbour-joining trees of genetic distances. Our lexical distance results confirmed the north/south dialectal subdivision of Corsican speeches described by linguists. No clear results were achieved with genetic distances because of the low number of loci for which data were available. Nevertheless, a tight northern cluster clearly emerged. When compared to other Mediterranean populations, Corsica showed a certain degree of differentiation, although not so marked as that of Sardinia. Corsica presented genetic affinities with Campania, Sicily, Liguria, Provence and Latium, while distances with Tuscany and Sardinia were larger. These results can be interpreted as a reflection of the prehistoric isolation of Corsica and the relative contribution to the island gene pool of prehistoric and historic invaders and immigrants from several populations.

We have studied cystic fibrosis from an evolutionary perspective by focusing on three main points: the high frequency of cystic fibrosis; the different spectrum of mutations that cause the disease in different areas of Europe; and the age of the delta F508 mutation. Several hypotheses have been suggested to explain the high frequency of cystic fibrosis. We argue that the most plausible is heterozygote resistance to cholera and to other dehydrating intestinal diseases. Different population sizes in the past could explain the higher diversity among cystic fibrosis mutations found in southern Europe. Three microsatellite loci are found close to the delta F508 mutation. The reconstruction of the original microsatellite haplotype in which delta F508 arose, and of the genealogy of the microsatellite haplotypes bearing the mutation, allowed us to date the mutation event at around 50,000 years ago.

Two hypervariable sequence segments in the control region of mitochondrial DNA were determined in samples of Bulgarians and Turks. The Turkish sample presented a higher degree of internal diversity, in terms of total number of variable nucleotides, as well as in the average pairwise nucleotide difference. Pairwise difference distributions were built for both samples, yielding smooth bell shapes in agreement with the Rogers and Harpending model. The Bulgarian and Turkish data were compared with several European and W. Asian Caucasoid populations (Basques, Tuscans, Sardinians, British, Middle Easterners and Indians). Mean pairwise differences suggest that a demographic expansion occurred sequentially in the Middle East, through Turkey, to the rest of Europe (Bulgaria included). Current mutation rate estimates date this expansion in times ranging between 50,000 and 100,000 years ago and, thus, would correspond to the arrival of anatomically modern humans in Europe. Sequence trees for segment I show that European and Middle Eastern sequences derived from the reference sequence. Coalescence times for segment I sequences agree with those predicted by pairwise distributions. Genetic trees were constructed between populations and revealed an extreme homogeneity between European samples.

An allele heterogeneity in a short tandem repeat at the human dihydrofolate reductase pseudogene (DHFRP2) was detected using non-denaturing gel electrophoresis and ethidium bromide staining. Sequence analysis of the allele, designated 9A, revealed the C to A substitution in the 8th AAAC repeat. A survey of 16 worldwide human populations showed that this mutation was spread through five continents at a relatively high frequency (up to p = 0.19 in Europeans). Some statistical parameters of forensic interest were also calculated (h, PD, EC and PIC) for this polymorphism. This type of heterogeneity stresses the complexity of STR variation.

The hypervariable segment I of the control region of the mtDNA (positions 16024-16383) was PCR-amplified from mouth scrape and hairs and sequenced in 45 unrelated individuals of pure matrilineal Basque descent. Twenty-seven different sequences were found, of which 21 are unique to the Basques. The allelic partition observed, together with resampling experiments, suggested that much more variation remained to be discovered. The mean pairwise difference in number of nucleotides between individuals was 3-15, a very low value. Moreover, the number of steps for the most parsimonious tree is very low compared to the number of different sequences. Both findings suggest that the Basque population was founded by a few lineages that diverged in a short time span. The number of nucleotide differences between individuals was shown not to be influenced by the distance between their birthplaces, thus validating the sampling strategy used a posteriori. The pairwise difference distribution agreed well with the three-parameter model proposed by Rogers & Harpending (1992). The parameter estimates found for the Basques implied that a demographic expansion (or perhaps two, given the bimodal shape of the distribution) took place sometime between 14500 and 42000 BP which is in agreement with archaeological data. Our sample was compared to other populations for which D-loop sequences were available through the Nei & Miller (1990) distance. In a neighbour-joining tree, all the Caucasoid samples, including the Basques, appeared tightly clustered, whereas African samples were the most distant to the Caucasoids and also the most heterogeneous. Although classical markers, such as blood groups and protein polymorphisms, clearly separate the Basques (and the Sardinians) from other European populations, this distinctiveness was not found using D-loop sequences.

Genetic evidence is consistent with the view that the Indo-European languages were propagated in Europe by the diffusion of early farmers. The existence of phylogenetic relationships between European populations speaking other languages has been proposed on linguistic and archaeological grounds, and is here tested by analyzing allele frequencies at ten polymorphic protein and blood group loci. Genetic distances between speakers of Basque and Caucasian languages are compared with those between controls, i.e. contiguous populations speaking Indo-European and Altaic. Although some statistical tests show an excess of genetic similarity between Basque and South Caucasian speakers, most results do not support their common origin. If the Basques and the Caucasian-speaking populations share common ancestors, recent evolutionary phenomena must have caused divergence between them, so that their gene frequencies do not appear more similar now than those of random pairs of populations separated by the same geographic distance.

The Pyrenees Mountains rise between France and Spain. At their western end live the Basques, one of the oldest populations in Europe. All the available genetic information (gene frequencies of blood groups, serum proteins, red cell enzymes, and HLA antigens) on Pyrenean populations has been gathered and subjected to two kinds of analysis: a discrete approach, in which eight separate populations have been defined according to linguistic and geographic criteria to compute genetic distances between them; and a continuous principal components analysis on gene frequencies interpolated to a regular grid. In the first approach the Pyrenean samples have also been compared to other Western European populations. Our results show that the Basque population is most genetically differentiated with respect to other Pyrenean and Western European populations. There is a strong genetic gradient along the mountain range (i.e., in an east-west direction); thus the mountains have not acted as barriers to gene flow. A Catalan-speaking sample, the Cerdanya, is slightly detached from its neighbors and seems closer to other European populations. This genetic picture together with linguistic, paleoanthropological, and archeological data points to a Mesolithic (or older) differentiation of the Cantabrian ancestors of the Basques. Moreover, the Basque genetic features are found in the northern slope of the Pyrenees far beyond the present Basque linguistic boundaries, in accordance with the most recent hypotheses on Pyrenean historical linguistics. The genetic consequences of the arrival of the first Indo-European-speaking peoples in the Iberian Peninsula are also studied; no clear genetic trace has been left of that population movement, except perhaps for the Cerdanya, an eastern valley that affords a passage between north and south.

The genetic peculiarity of the Basque population has long been noted. We aim to describe Basque distinctiveness in space and assess the internal Basque heterogeneity. All these aspects are relevant to the question of the origin of Basques. After a thorough literature search, a data base was created containing all the available data on gene frequencies in the Iberian Peninsula and France. Twenty-nine systems, comprising 71 alleles, were used to carry out a principal component (PC) analysis. The results show a sharp peak in the first PC in the Basque area, which remains even when the geographic scope is widened to include western Europe. As demonstrated by "wombling" analysis, the steeper slope in the first PC is found to the east of the Basque area, along the Pyrenees. Measures of genetic heterogeneity (such as FST values) within the Basque country, as compared to those for non-Basques, do not show a particular internal substructuration in the Basque population. The genetic results support a scenario in which the Basques are the product of in situ differentiation around the time of the Last Glacial Maximum (18,000 B.P.), in agreement with archaeological and linguistic data. Isolation from the surrounding populations has allowed the differentiation to last for millennia, but has erased the differences existing among Basques.

Matrimonial mobility in Catalonia was studied using 1986 census data. Comarca (a geographic division) of birth was used as the population unit, and a measure of affinity (a statistical distance) between comarques in spouse geographic origin was defined. This distance was analyzed with multivariate methods drawn from numerical taxonomy to detect any discontinuities in matrimonial mobility and gene flow between comarques. Results show a three-level pattern of gene flow in Catalonia: (1) a strong endogamy within comarques; (2) a 100-km matrimonial circle around every comarca; and (3) the capital, Barcelona, which attracts migrants from all over Catalonia. The regionalization in matrimonial mobility follows the geographically clear-cut groups of comarques almost exactly.