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Biomedical subjects

J A Castro

Publications and source records attributed to J A Castro.

At least 19 recordsLinked to original sources
PubMed2006

Mitochondrial DNA sequence variation in Jewish populations.

Sequence analysis of HVRI and HVRII mitochondrial DNA was carried out on 107 Jewish samples from Ashkenazi, Oriental, North African, and Sephardic origins. Control region sequences were assigned to a haplogroup by means of the analysis of the RFLP motif -7025 AluI or by using sequence motifs. A total of 88 different haplotypes were observed with a lower incidence of unique haplotypes (68.2%) than in other populations. Four individuals with one position of sequence heteroplasmy at nucleotides 16093, 16134, 16169, and 235, respectively, were detected. The mean pairwise difference in the Jewish population was 9.7 nucleotides. The gene diversity was 0.996, and the random match probability was 1.3%. When the data were compared with the autosomal and Y-chromosome markers previously studied in these populations, sex-specific differences could be observed in the Jewish populations. This fact must be taken into account for choosing suitable databases to correctly weigh the value of the evidence of a mtDNA and/or Y profile match.

Africa, Northern↗
PubMed2006

Differential maternal and paternal contributions to the genetic pool of Ibiza Island, Balearic Archipelago.

We report on a comparison of the genetic diversity between Ibiza and the population of the other Balearic islands and also between the archipelago with respect to circum-Mediterranean populations. For such a comparison, autosomal and Y-chromosome STRs, as well as mtDNA sequence data analyzed from the same individuals, were studied. Analysis of 14 autosomal STRs showed that Ibiza had significant differentiation with respect to other Balearic populations and also with respect to insular and continental populations from the Mediterranean area. Nevertheless, the results obtained from the analysis of eight Y-STRs showed a high level of genetic homogeneity for eight western Mediterranean populations. On the other hand, these populations did not show a compacted group when mtDNA diversity was analyzed, since they showed genetic differentiation among them. The analyses of haplotypes shared between populations indicated that mtDNA haplotypes have drifted to higher frequencies than the Y chromosome. This fact could be due to a shared recent history between Ibiza and other western Mediterranean populations, with numerous male displacements originated by wars and, especially, commercial relations. The results of mtDNA from the Ibiza population could be due to a maternal Carthaginian/Phoenician founder effect, together with genetic drift, in accordance with the historical and demographic data of the area.

Chromosomes, Human, Y↗
PubMed2006

Prevalence of HFE C282Y and H63D in Jewish populations and clinical implications of H63D homozygosity.

The frequencies of C282Y and H63D mutations of the HFE gene vary between different populations. A previous study showed an unexpectedly high H63D frequency in Chuetas (a population of Jewish descent). The present study addressed the question of the distribution of these mutations in Jewish populations from different origins and studied the possible causes of the high H63D frequency in Chuetas. Moreover, to improve the understanding of the controversial relationship between H63D homozygosity and iron overload, a group of patients with altered iron metabolism were studied. The high frequency of H63D mutation in Chuetas is not due to a high prevalence of this mutation in Sephardic Jews. Jewish populations have low C282Y and moderate H63D frequencies, suggesting slight gene flow from their surrounding populations. In accordance with historical and demographic data, genetic drift is the most probable cause for the singular H63D frequency in Chuetas. Clinically, this study of H63D homozygotes supports the conclusion that this genotype must be taken into account, because it confers an increased risk of iron overload and therefore genetic susceptibility to developing hereditary hemochromatosis or to aggravating other diseases.

Alleles↗
PubMed2005

Evolutionary analysis of genetic variation observed in citrus tristeza virus (CTV) after host passage.

We have studied the genetic variability in two genes (p18 and p20) from two groups of Citrus tristeza virus (CTV) isolates. One group (isolates T385, T317, T318, and T305) was derived from a Spanish source by successive host passages while the other (isolates T388 and T390) was obtained after aphid transmission from a Japanese source. A total of 274 sequences were obtained for gene p18 and 451 for p20. In the corresponding phylogenetic trees, sequences derived from the severe isolates (T318, T305, and T388) clustered together and separately from those derived from mild or moderate isolates (T385, T317, and T390), regardless of their geographic origin. Hierarchical analyses of molecular variance showed that up to 53% of the total genetic variability in p18 and up to 87% of the variation in p20 could be explained by differences in the pathogenicity features of the isolates. Neutrality tests revealed that different selection forces had been acting between isolates and between genes, with purifying selection being suggested for p18 from isolates T385 and T390 and for p20 from isolates T385, T317, and T388, and balancing selection for p18 from isolates T318, T305, and T388 and for p20 from isolates T318 and T390. Furthermore, several models of codon selection were observed, with purifying selection being the most notable one, compatible with low effective population size of the virus populations resulting from transmission bottlenecks. We found no evidence of recombination playing a significant role during p18 and p20 evolution in these isolates. These results suggest that hosts can be an important evolutionary factor for CTV isolates.

Animals↗
PubMed2005

Mitochondrial DNA HVRI variation in Balearic populations.

The Balearic archipelago (Majorca, Minorca, and Ibiza islands and the Chuetas, a small and inbred community of descendants of Sephardic Jews) and Valencia were studied by means of the sequencing of a 404-bp segment of hypervariable region I (HVRI) mtDNA in 231 individuals. In total, 127 different haplotypes defined by 92 variable positions were identified. The incidence of unique haplotypes was very low, especially in Ibiza and the Chuetas. A remarkable observation in the Chueta community was the high frequency (23%) of preHV-1, a Middle Eastern lineage that is closely related, though not identical, to many others found at high frequencies in different Jewish populations. The presence of this haplogroup convincingly supported the Jewish origin of the Chueta community. The studied populations showed a reduced African contribution, and no individuals were detected with North African haplogroup U6, indicating a lack of maternal contribution from the Moslem settlement to these populations. Only Ibiza showed a lower diversity, indicating a possible genetic drift effect, also supported by the historical information known about this island. The variability in the sequence of mtDNA hypervariable region I correlated well with the existing information from the populations, with the exception of that of the Y-chromosome, which could indicate a differential contribution of the maternal and paternal lineages to the genetic pool of the Balearic Islands. The phylogenetic trees showed the intermediate position of the Chueta population between the Middle Eastern and Majorcan samples, confirming the Jewish origin of this population and their Spanish admixture.

Anthropology, Physical↗
PubMed2004

Fitness and life-history traits of the two major mitochondrial DNA haplotypes of Drosophila subobscura.

Mitochondrial DNA restriction site analyses on natural populations of Drosophila subobscura have proved the existence of two common, coexisting haplotypes (I and II), as well as a set of less frequent ones derived from them. To explain this distribution, experiments to date point practically to all possible genetic mechanisms being involved in the changes of gene frequencies (cytonuclear coadaptation, direct natural selection on mtDNA and genetic drift). In an attempt to find differences that help to understand the dynamics of these haplotypes and to detect the effect of selection, we measured certain fitness components and life-history traits (egg-larva and larva-adult viabilities and developmental times, longevity, resistance to desiccation and optimal density) of the two main haplotypes I and II when maintained in laboratory population cages. As a general trend, haplotype II showed a higher net fitness than haplotype I, which explains the superiority of haplotype II over haplotype I in experimental populations but not their coexistence in nature, where additional factors must be considered.

Animals↗
PubMed2003

Rat breast microsomal biotransformation of ethanol to acetaldehyde but not to free radicals: its potential role in the association between alcohol drinking and breast tumor promotion.

We recently showed that mammary cytosolic xanthineoxidoreductase had the ability to bioactivate ethanol (EtOH) to acetaldehyde (AC) and free radicals. In the present study, we report that the microsomal fraction also biotransforms EtOH to AC. One pathway requires NADPH and the others do not. Both need oxygen. The NADPH-dependent pathway is not inhibited by CO:O(2) (80:20) or SKF 525A and that excludes the participation of cytochrome P450. It is inhibited by diethyldithiocarbamate (DDTC), sodium azide, and diphenyleneiodonium (DPI) but not by desferrioxamine, which suggests a possible role of a non-iron copper-requiring flavoenzyme. The process was partially inhibited by thiobenzamide (TBA), methylmercaptoimidazole (MMI), and nordihydroguaiaretic acid (NDG) but not by dapsone, aminotriazole, or indomethacin. These results suggest the potential participation of flavine monooxygenase and of lipooxygenase or of peroxidases/oxidases having similar characteristics but not of lactoperoxidase or cyclooxygenase. The pathway not requiring NADPH could also be partially inhibited by DDTC, NDG, azide, DPI, and TBA or MMI but not by the other chemicals. Little activity proceeds under nitrogen. Oxidases or peroxidases might be involved. No formation of 1-hydroxyethyl radicals was detected either in the presence or absence of NADPH. The nature of the EtOH bioactivating enzymes involved remains to be established. However, the fact remains that an activation of EtOH to AC was found in mammary tissue and could have a significant effect in some stages of the process of breast tumor promotion by EtOH.

Acetaldehyde↗
PubMed2002

Nifurtimox biotransformation to reactive metabolites or nitrite in liver subcellular fractions and model systems.

Liver microsomal (mic); nuclei (N) and mitochondria (mit) anaerobically nitroreduce Nifurtimox (Nfx) in the presence of NADPH generating system. Simultaneous formation of small amounts of nitrite was observed in microsomes and nuclei but not in mitochondria. The microsomal nitroreductase activity was enhanced by the presence of flavine-adenine-dinucleotide disodium salt (FAD), was not inhibited by CO and was significantly inhibited by diphenyleneiodonium (DPI). In the microsomal NADPH-dependent fraction nitrite formation was null in the presence of FAD, DPI and under air and was partially inhibited by pure CO. Pure human cytochrome P450 reductase in the presence of NADPH significantly nitroreduced Nfx and produced small amounts of nitrite. The nitroreductive process was significantly enhanced by FAD but the nitrite formation became null. FAD itself was able to chemically nitroreduce Nfx without production of nitrite. NADPH generating system enhanced the FAD nitroreductive effect and led to small production of nitrite. Formation of reactive metabolites and nitric oxide during Nfx metabolism might contribute to its toxicity.

Anaerobiosis↗
PubMed2002

Alcohol induction of liver nuclear ethanol and N-nitrosodimethylamine metabolism to reactive metabolites.

In previous studies from our laboratory we reported the presence in highly purified liver nuclei, free of contamination with other organelles, of an ethanol metabolizing system (NEMS) able to lead to acetaldehyde and 1-hydroxyethyl free radicals (1HEt). In the present study we tested whether this NEMS is inducible by chronic alcohol administration to rats and whether these nuclei also have increased ability to bioactivate N-nitrosodimethylamine (NDMA). Sprague Dawley male rats (125-150g) were fed with a nutritionally adequate liquid diet containing alcohol to provide 36% of total energy (standard Lieber-De Carli rat diet), for 28 days. Controls received an isocaloric diet without alcohol. Animals were sacrificed, livers were excised and microsomes and purified nuclear fractions were prepared. Both microsomes and nuclei from treated animals had significantly increased ability compared to controls, to biotransform ethanol to acetaldehyde using NADPH as cofactor under an air atmosphere. Both organelles also exhibited significantly increased capacity compared to controls, to bioactivate NDMA to formaldehyde and to reactive metabolites that bind covalently to proteins. Nuclear preparations from control animals were also able to metabolize NDMA to formaldehyde and reactive metabolites. Results indicate that liver nuclei may have a CYP2E1 able to bioactivate both NDMA and EtOH and that these processes are being induced by chronic alcohol drinking. The bioactivation of these xenobiotics to reactive metabolites in the neighborhood of nuclear proteins and DNA might have significant toxicological implications.

Acetaldehyde↗
PubMed2002

Rat ventral prostate microsomal biotransformation of ethanol to acetaldehyde and 1-hydroxyethyl radicals: its potential contribution to prostate tumor promotion.

Rat ventral prostate microsomal fraction was able to biotransform ethanol to acetaldehyde and 1-hydroxyethyl radicals (1HEt) in the presence of NADPH and oxygen. The enzymatic processes involved were not inhibited by desferrioxamine, CO, SKF 525A, 4-methylpyrazole, or polyclonal antibody against P450 reductase but they were significantly inhibited by diethyldithiocarbamate, 2-mercapto-1-methylimidazol, thiobenzamide, or diphenyleneiodonium chloride. Results would suggest the partial participation in these ethanol bioactivation processes of flavin containing monooxygenase (FMO) and/or other flavin dependent oxidases/peroxidases and of a non-iron metal-containing enzymes. Acetaldehyde and free radicals production by prostate microsomal fraction might potentially contribute to tumor promotion in heavy alcohol drinkers.

Acetaldehyde↗
PubMed2002

Genetic variability at 14 STR loci in the Puna population of north western Argentina.

Frequency data of the short tandem repeat (STR) loci D3S1358, vWA, FGA, D8S1179, D21S11, D18S51, D5S818, D13S317, D7S820, HUMTH01, D4S243, D18S535, HUMF13A1 and D12S391 were determined in the Puna population (Andean region from north western Argentina). In this study, 5 out of the 14 loci did not meet Hardy-Weinberg expectations. The excess of homozygotes observed in most of the markers could be due to a Wahlund effect and/or inbreeding. The frequencies were significantly different from those of other compared populations from Europe and America. Forensic parameters indicated that the 14 loci studied in the Puna region are highly discriminating, but the lack of Hardy-Weinberg equilibrium in some of the markers must be taken into account in the application of these results to paternity and forensic casework.

Alleles↗
PubMed2002

Distribution of HFE C282Y and H63D mutations in the Balearic Islands (NE Spain).

The HFE gene contains two main missense mutations: C282Y and H63D. Individuals with these mutations carry a risk of developing hereditary haemochromatosis (HH). The common form of this disease is due to homozygosity for the C282Y mutation. Population studies have shown the variation of the prevalence of these mutations in different countries and ethnic groups. The purposes of this current study were to determine the prevalence of the C282Y and H63D mutations in the Balearic Islands and the genotypic characterization of patients diagnosed with HH, as well as those with iron overload and liver diseases. A total of 1330 Balearic chromosomes were analyzed. The results showed that the populations of the Balearic Islands were not homogeneous. No C282Y carriers were observed in a group of descendants of Majorcan Jews (Chuetas) and the frequency was very low in Minorca (1.2%) in comparison with the other islands of Majorca (4.7%) and Ibiza (6.5%). The carrier frequency of the H63D mutation was similar in the three islands and very high (43.1%) in the descendants of Majorcan Jews. The study of patients was carried out in 129 individuals. The homozygous C282Y genotype was the principal one involved in hereditary haemochromatosis (90%), whereas the other HH patients were C282Y/H63D compound heterozygous and H63D homozygous.

Adolescent↗
PubMed2002

HLA polymorphism in a Majorcan population of Jewish descent: comparison with Majorca, Minorca, Ibiza (Balearic Islands) and other Jewish communities.

'Chueta' was the name given to the Catholic descendants of Jewish victims of the last Spanish Inquisition process in Majorca Island in the western Mediterranean. We have studied the allele distribution of HLA-A, -B, -Cw, -DRB1 and -DQB1 loci of 103 random, healthy, unrelated individuals belonging to the ancient Majorcan Jewish community, known locally as Chuetas, and 589 individuals from the Balearic population selected because of their typical Balearic - Majorca, Minorca or Ibiza - lineages and according to their ancestor's place of birth. Our aim was to establish the genetic relationship between Majorcan Chuetas, and Balearic and other Jewish and Mediterranean populations. Our results have shown that, to a remarkable extent, they have retained their biological identity, with a unique pattern, in terms of gene and haplotype frequencies, separate from the other populations of Majorca. The Chuetas were found to be more related to Moroccan and Libyan Jews than other Majorcans. Characteristic Jewish haplotypes, A26-B38-DRB1*13, A24-B38-DRB1*11, A1-B52-DRB1*15/16, were found in our study. Some peculiarities were observed in the distribution of common haplotypes among the three main Balearic Islands. The Ibizan population was genetically different from the other Balearic populations, with a high frequency of some haplotypes, for example, A29-Cw*16-B44-DRB1*07-DQB1*03; A1-Cw*07-B8-DRB1*03-DQB1*02. We also found a new haplotype, A25-Cw*12-B39-DRB1*11-DQB1*03(3.5%), in Ibizans and a more limited variability in the HLA alleles that were expressed, perhaps because of genetic isolation. The genetic diversity of the populations from Majorca and Minorca were similar and more related to the mainland Spanish population.

Alleles↗
PubMed2002

Linkage disequilibria between mtDNA haplotypes and chromosomal arrangements in a natural population of Drosophila subobscura.

The association between mtDNA haplotypes and chromosomal arrangements in a natural population of Drosophila subobscura from Calvia (Balearic Islands, Spain) was studied in order to search for linkage disequilibria, in an attempt to explain the populational dynamics of the mtDNA haplotypes of this species in nature. The presence of Wolbachia was not detected. Two main haplotypes (I and II) were found, as well as a series of less common ones. The Tajima D-test seemed to indicate some kind of seasonal population bottleneck. An analysis of linkage disequilibrium and factorial analysis of correspondences detected an association between haplotype I and the J(ST) inversion and haplotype II and the J(1) inversion.

Animals↗