Biomedical subjects

F Calafell

Publications and source records attributed to F Calafell.

At least 73 records · Page 4Linked to original sources

PubMed1997

Detection of major genes underlying several quantitative traits associated with a common disease using different ascertainment schemes.

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.

Chromosome Mapping↗

PubMed1997

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.

Animals↗

PubMed1997

Microsatellite variation and the differentiation of modern humans.

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.

Analysis of Variance↗

PubMed1997

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.

DNA, Mitochondrial↗

PubMed1997

Cystic fibrosis mutations and associated haplotypes in Bulgaria - a comparative population genetic study.

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.

Bulgaria↗

PubMed1997

Genetic history of cystic fibrosis mutations in Italy. I. Regional distribution.

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.

Cystic Fibrosis↗

PubMed1997

A tale of two islands: population history and mitochondrial DNA sequence variation of Bioko and São Tomé, Gulf of Guinea.

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.

Atlantic Islands↗

PubMed1997

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.

Africa, Northern↗

PubMed1997

Seventy-five nuclear DNA polymorphisms in an Italian sample: a comparative worldwide study.

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.

Biological Evolution↗

PubMed1996

Sequence diversity of the control region of mitochondrial DNA in Tuscany and its implications for the peopling of Europe.

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.

Base Sequence↗

PubMed1996

Genetic and geographical variability in cystic fibrosis: evolutionary considerations.

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.

Cystic Fibrosis↗

PubMed1996

Identification of a base pair substitution at the tetranucleotide tandem repeat locus DHFRP2 (AAAC)n in a worldwide survey.

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.

Alleles↗

PubMed1996

Geographic homogeneity and non-equilibrium patterns of mtDNA sequences in Tuscany, Italy.

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.

Analysis of Variance↗

PubMed1996

Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24.

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.

Adolescent↗

PubMed1996

Geographic variation in human mitochondrial DNA control region sequence: the population history of Turkey and its relationship to the European populations.

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.

Base Sequence↗

PubMed1996

From Asia to Europe: mitochondrial DNA sequence variability in Bulgarians and Turks.

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.

Base Sequence↗

PubMed1996

High mitochondrial sequence diversity in linguistic isolates of the Alps.

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.

DNA, Mitochondrial↗

PubMed1995

Human mitochondrial DNA variation and the origin of Basques.

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.

Base Sequence↗