Biomedical subjects

Jaume Bertranpetit

Publications and source records attributed to Jaume Bertranpetit.

13 recordsLinked to original sources

PubMed2003

Evidence for a genetic discontinuity between Neandertals and 24,000-year-old anatomically modern Europeans.

During the late Pleistocene, early anatomically modern humans coexisted in Europe with the anatomically archaic Neandertals for some thousand years. Under the recent variants of the multiregional model of human evolution, modern and archaic forms were different but related populations within a single evolving species, and both have contributed to the gene pool of current humans. Conversely, the Out-of-Africa model considers the transition between Neandertals and anatomically modern humans as the result of a demographic replacement, and hence it predicts a genetic discontinuity between them. Following the most stringent current standards for validation of ancient DNA sequences, we typed the mtDNA hypervariable region I of two anatomically modern Homo sapiens sapiens individuals of the Cro-Magnon type dated at about 23 and 25 thousand years ago. Here we show that the mtDNAs of these individuals fall well within the range of variation of today's humans, but differ sharply from the available sequences of the chronologically closer Neandertals. This discontinuity is difficult to reconcile with the hypothesis that both Neandertals and early anatomically modern humans contributed to the current European gene pool.

Animals↗

PubMed2003

Dynamics of CAG repeat loci revealed by the analysis of their variability.

In order to understand the dynamics of the expressed single tandem repeat trinucleotides (most of them involved in pathological expansion), the diversity in 10 different loci (SCA1, SCA2, SCA3, SCA6, SCA8, SCA12, DRPLA, HD, KCNN3, and NCOA3) was analyzed in four major human groups (Africans, Europeans, Indians, and East Asians). The present analysis intends to disentangle population-based from genetic-based factors having shaped STR (trinucleotide) variation and to recognize, for each locus, the specific rate and pattern of mutation (bias toward expansion or contraction, constraints on allele size), and the footprints of selection. Population differences account for a very small part of the total variation, but a clear footprint appears of population growth after a bottleneck in all non-African populations, giving support to the out-of-Africa model of modern humans. Most of the diversity is found among loci, and different dynamics are inferred for each of them. SCA2 and SCA3 follow an unrestricted stepwise mutation model, while the rest of loci are found under allele size constrictions and a bias to expansion (SCA1, SCA6, HD, and KCNN3), contraction (SCA12, DRPLA, and NCOA3), or unbiased (SCA8).

Alleles↗

PubMed2003

Prion susceptibility and protective alleles exhibit marked geographic differences.

A total of 616 chromosomes from control individuals of all major continental groups, and six individuals affected by either Creutzfeldt-Jakob disease (CJD) or fatal familial insomnia (FFI), were typed with a new single-reaction protocol method and were also sequenced, with total reproducibility to screen variation at important positions (385A>G: M129V and 655G>A: E219K) in the human prion protein gene (PRNP). We have found, for the first time, that 129V allele is highly represented in some populations from the Americas, and that 129M and 129V are in similar frequencies in Africa. The 129M susceptibility allele was found at high frequencies in Old World populations, very high in the Pacific ( approximately 81%) and up to 93% in Central and East Asia, but at a low frequency (approximately 30%) in Native Americans. The protective 219L allele was restricted to Asian and Pacific populations. Susceptibility alleles exhibit marked geographic differences in frequency, and thus, differences in probability to develop prion diseases.

Africa↗

PubMed2003

Association study between Alzheimer's disease and genes involved in Abeta biosynthesis, aggregation and degradation: suggestive results with BACE1.

BACKGROUND: Amyloid beta-peptide (Abeta) biosynthesis, aggregation and degradation constitute three important steps to consider in the study of pathological mechanisms involved in Alzheimer's disease (AD). Several proteins have been suggested as involved in each of these processes: proteolytic cleavage of the amyloid precursor protein by the beta-site APP cleaving enzyme (BACE), increased amyloid fibril formation by the activity of the acetylcholinesterase (ACHE gene), and degradation of Abeta aggregates by the plasmin system have been exhaustively documented. METHODS: A case-control design was used to evaluate the possible association between candidate genes involved in these three processes and AD. We analysed three polymorphisms located at the BACE1 gene, one polymorphism at the ACHE gene, and two variants located at the tissue plasminogen activator and plasminogen activator inhibitor-1 (genes TPA and PAI- 1, respectively), both part of the plasmin system. RESULTS: We found an association between BACE1 exon 5 GG genotype and AD (age-and gender-adjusted odds ratio = 2.14, P =0.014). Although a similar association was reported previously by Nowotny and collaborators only in subjects carrying the epsilon4-allele of the apolipoprotein E gene (APOE), we did not detect this effect. However,when we combined our results with those previously reported, a clear increase of the risk to develop AD appeared in subjects carrying both the BACE1 exon 5 GG genotype and the APOE epsilon4-allele (crude OR = 2.2, P = 0.004). CONCLUSION: These data suggest a possible genetic relation between BACE1 and AD.

3' Untranslated Regions↗

PubMed2003

Spatial patterns of cystic fibrosis mutation spectra in European populations.

Cystic fibrosis (CF) is the most frequent severe recessive disorder in European populations. We have analyzed its mutation frequency spectrum in 94 European, North African and SW Asian populations taken from the literature. Most major mutations as well as the incidence of CF mutations showed clinals patterns as demonstrated by autocorrelogram analysis. More importantly, measures of mutation diversity did also show clinal patterns, with mutation spectra being more diverse in southern than in northern Europe. This increased diversity would imply roughly a three-fold long-term effective population size in southern than in northern Europe. Distances were computed among populations based on their CF mutation frequencies and compared with distances based on other genic regions. CF-based distances correlated with mtDNA but not with Y-chromosome-based distances, which may be a consequence of the relatively homogeneous CF mutation frequencies in European populations.

Cystic Fibrosis↗

PubMed2003

Joint analysis of candidate genes related to Alzheimer's disease in a Spanish population.

BACKGROUND: Besides the repeated association between the epsilon 4 allele of the apolipoprotein E and Alzheimer's disease, several candidate genes have been analysed with inconsistent results. Most of these studies have examined only one or two polymorphisms in a defined population, which provides a lack of a general view of the Alzheimer's disease genetic component. OBJECTIVE: To overcome this limitation, nine polymorphisms in seven different candidate genes (A2M, ACT, APOE, APP, BH, HSP70-2, and IL1-A) were genotyped. METHODS: The sample comprised 112 Alzheimer's disease patients and 89 controls from Spain. Since haplotype reconstruction may add power to association studies, we also tested for linkage disequilibrium within the A2M and APOE genes. RESULTS: Except for the APOE gene, allele and genotype frequencies were not different between cases and controls, even when stratifying for the APOE genotype. CONCLUSION: The present results suggest that future association studies should be performed using a battery of polymorphisms in different and new candidate genes, taking into account the linkage disequilibrium in the region.

Alzheimer Disease↗

PubMed2003

HSP70-2 (HSPA1B) is associated with noncognitive symptoms in late-onset Alzheimer's disease.

Neuropsychiatric manifestations are common in Alzheimer's disease (AD) and their phenotypic expression might be related to physiopathological and genetic causes. Multiple studies have implicated oxidative stress to the pathogenesis and possible etiology of AD. One of the mechanisms to protect cells from oxidative stress is the expression of heat-shock proteins (HSP). HSPA1B (alternatively known as HSP70-2) has been related to AD pathophysiology. In the present analysis, 77 AD patients were classified according to their cognitive status with the Neuropsychiatric Inventory and were genotyped for an insertion/deletion (A1/A2) polymorphism. The A2 allele conferred a significant increase of psychiatric morbidity in an allele-dose manner (P < .05). This pattern can be attributed to all AD stages and the severity of the behavioral disturbances was higher for those patients carrying one or two A2 alleles. These results indicate a possible association between the A2 allele and an overexpression of noncognitive symptoms in AD.

Age Factors↗

PubMed2002

A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity.

Variants of different Class I alcohol dehydrogenase (ADH) genes have been shown to be associated with an effect that is protective against alcoholism. Previous work from our laboratory has shown that the two sites showing the association are in linkage disequilibrium and has identified the ADH1B Arg47His site as causative, with the ADH1C Ile349Val site showing association only because of the disequilibrium. Here, we describe an initial study of the nature of linkage disequilibrium and genetic variation, in population samples from different regions of the world, in a larger segment of the ADH cluster (including the three Class I ADH genes and ADH7). Linkage disequilibrium across approximately 40 kb of the Class I ADH cluster is moderate to strong in all population samples that we studied. We observed nominally significant pairwise linkage disequilibrium, in some populations, between the ADH7 site and some Class I ADH sites, at moderate values and at a molecular distance as great as 100 kb. Our data indicate (1) that most ADH-alcoholism association studies have failed to consider many sites in the ADH cluster that may harbor etiologically significant alleles and (2) that the relevance of the various ADH sites will be population dependent. Some individual sites in the Class I ADH cluster show Fst values that are among the highest seen among several dozen unlinked sites that were studied in the same subset of populations. The high Fst values can be attributed to the discrepant frequencies of specific alleles in eastern Asia relative to those in other regions of the world. These alleles are part of a single haplotype that exists at high (>65%) frequency only in the eastern-Asian samples. It seems unlikely that this haplotype, which is rare or unobserved in other populations, reached such high frequency because of random genetic drift alone.

Alcohol Dehydrogenase↗

PubMed2002

PKLR- GBA region shows almost complete linkage disequilibrium over 70 kb in a set of worldwide populations.

Haplotype diversity in a genomic region of approximately 70 kb in 1q21 between genes PKLR and GBA was characterized by typing one single nucleotide polymorphism (SNP) in PKLR, two SNPs in GBA and one short tandem repeat polymorphism (STRP) in PKLR in 1792 chromosomes from 17 worldwide populations. Two other SNPs in GBA were typed in three African populations. Most chromosomes carried one of either two phylogenetically distinct haplotypes with different alleles at each site. Allele diversity at the STRP was tightly linked to haplotype background. Linkage disequilibrium (LD) was highly significant for all SNP pairs in all populations, although it was, on average, slightly higher in non-African populations than in sub-Saharan Africans. Variation at PKLR-GBA was also tightly linked to that at the GBA pseudogene, 16 kb downstream from GBA. Thus, a 90 kb-long LD block was observed, which points to a low recombination rate in this region. Detailed haplotype phylogeny suggests that the chimpanzee GBA haplotype is not one of the two most frequent haplotypes. Based on variability at the PKLR STRP and on the geographical distribution of LD, the expansion of the two main haplotypes may have predated the "Out of Africa" expansion of anatomically modern humans. LD and STRP variability in non-Africans are approximately 87% of those in Africans, in contrast with other loci; this implies that the "out of Africa" bottleneck may have had a broad distribution of effects across loci.

Africa↗

PubMed2002

Molecular phylogeny and evolution of the extinct bovid Myotragus balearicus.

Myotragus balearicus was a dwarf artiodactyl endemic to the Eastern Balearic Islands, where it evolved in isolation for more than 5 million years before becoming extinct between 3640 and 2135 cal BC (calibrated years BC). Numerous unusual apomorphies obscure the relationship between Myotragus and the extant Caprinae. Therefore, genetic data for this species would significantly contribute to the clarification of its taxonomic position. In this study, we amplify, sequence, and clone a 338-base pair (bp) segment of the mitochondrial cytochrome b (cyt b) gene from a >9Kyr Myotragus subfossil from la Cova des Gorgs (Mallorca). Our results confirm the phylogenetic affinity of Myotragus with the sheep (Ovis) and the takin (Budorcas). In each tree, the Myotragus branch is long in comparison with the other taxa, which may be evidence of a local change in the rate of evolution in cyt b. This rate change may be due to in part to an early age of first reproduction and short generation time in Myotragus, factors that are potentially related to the extreme reduction in size of the adult Myotragus as compared to the other Caprinae.

Animals↗

PubMed2002

Determination of haploid DNA sequences in humans: application to the glucocerebrosidase pseudogene.

Variation analyses in the human genome at the sequence level, especially human genetic population analysis and genetic epidemiology, are hampered by the difficulty to ascertain haplotypes on autosomal regions. We have designed a new methodological approach to obtain autosomal haploid sequences from diploid organisms. First, genotypes are unambiguously determined through long-range PCR and diploid DNA sequencing. Second, cloning the whole PCR-amplified segment and sequencing a single clone for those fragments that presented a heterozygous position discern the allelic phase. The second allele is deduced from the genotype, and the phase reconfirmed by sequencing a second clone. A hundred human chromosomes were analysed for a 5.4 kb encompassing the glucocerebrosidase pseudogene on human chromosome 1. Haplotypes were unambiguously ascertained for all samples. The manner to combine the used techniques makes this approach a novelty. Haploid sequences from diploid organisms are obtained in a less time consuming and more accurate manner than in other used procedures.

Glucosylceramidase↗

PubMed2002

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Evolution, Molecular↗

PubMed2001

Can a place of origin of the main cystic fibrosis mutations be identified?

The genetic background of the mutations that most often cause cystic fibrosis (CF) is different from that of non-CF chromosomes in populations of European origin. It is not known whether these haplotype backgrounds could be found at high frequencies in populations in which CF is, at present, not common; such populations would be candidates for the place of origin of CF mutations. An analysis of haplotypes of CF transmembrane conductance regulator, together with their variation in specific CF chromosomes, in a worldwide survey of normal chromosomes shows (1) a very low frequency or absence of the most common CF haplotypes in all populations analyzed and (2) a strong genetic variability and divergence, among various populations, of the chromosomes that carry disease-causing mutations. The depth of the gene genealogy associated with disease-causing mutations may be greater than that of the evolutionary process that gave rise to present-day human populations. The concept of "population of origin" lacks either spatial or temporal meaning for mutations that are likely to have been present in Europeans before the ethnogenesis of present populations; subsequent population processes may have erased the traces of their geographic origin.

Cystic Fibrosis↗