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J Bertranpetit

Publications and source records attributed to J Bertranpetit.

At least 19 recordsLinked to original sources
PubMed2006

Extreme population differences across Neuregulin 1 gene, with implications for association studies.

Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia in recent years since its first association with the disease in an Icelandic population. Since then, many association studies have analysed allele and haplotype frequencies in distinct populations yielding varying results: some have replicated the association, although with different alleles or haplotypes being associated, whereas others have failed to replicate the association. These contradictory results might be attributed to population differences in allele and haplotype frequencies. In order to approach this issue, we have typed 13 SNPs across this large 1.4 Mb gene, including two of the SNPs originally found associated with schizophrenia in the Icelandic population, the objective being to discover if the underlying cause of the association discrepancies to date may be due to population-specific genetic variation. The analyses have been performed in a total of 1088 individuals from 39 populations, covering most of the genetic diversity in the human species. Most of the SNPs analysed displayed differing frequencies according to geographical region. These allele differences are especially relevant in two SNPs located in a large intron of the gene, as shown by the extreme F(ST) values, which reveal genetic stratification correlated to broad continental areas. This finding may be indicative of the influence of some local selective forces on this gene. Furthermore, haplotype analysis reveals a clear clustering according to geographical areas. In summary, our findings suggest that NRG1 presents extreme population differences in allele and haplotype frequencies. We have given recommendations for taking this into account in future association studies since this diversity could give rise to erroneous results.

Gene Frequency↗
PubMed2005

Haplotype tagging efficiency in worldwide populations in CTLA4 gene.

The cytotoxic T lymphocyte antigen 4 (CTLA4) acts as a potent negative regulator of T-cell response, and has been suggested as a pivotal candidate gene for autoimmune disorders such as Graves' disease, type 1 diabetes and autoimmune hypothyroidism, among others. Several single-nucleotide polymorphisms (SNPs) have been proposed as the susceptibility variants, or to be in strong linkage disequilibrium (LD) with the variant. Nevertheless, contradictory results have been found, which may be due to lack of knowledge of the genetic structure of CTLA4 and its geographic variation. We have typed 17 SNPs throughout the CTLA4 gene region in order to analyze the haplotype diversity and LD structure in a worldwide population set (1262 individuals from 44 populations) to understand the variation pattern of the region. Allele and haplotype frequency differentiation between populations is consistent with genomewide averages and points to a lack of strong population-specific selection pressures. LD is high and its pattern is not significantly different within or between continents. However, haplotype composition is significantly different between geographical groups. A continent-specific set of haplotype tagging SNPs has been designed to be used for future association studies. These are portable among populations, although their efficiency might vary depending on the population haplotype spectrum.

Alleles↗
PubMed2005

Ethiopia: between Sub-Saharan Africa and western Eurasia.

Ethiopia is central to population genetic studies investigating the out of Africa expansion of modern humans, as shown by Y chromosome and mtDNA studies. To address the level of genetic differentiation within Ethiopia, and its relationship to Sub-Saharan Africa and Eurasia, we studied an 8 kb segment of the X-chromosome from 72 chromosomes from the Amhara, Oromo and Ethiopian Jews, and compared these results with 804 chromosomes from Middle Eastern, African, Asian and European populations, and 22 newly typed Saharawi. Within Ethiopia the two largest ethnic groups, the Amhara and Oromo, were not found to be statistically distinct, based on an exact test of haplotype frequencies. The Ethiopian Jews appear as an admixed population, possibly of Jewish origin, though the data remain equivocal. There is evidence of a close relationship between Ethiopian and Yemenite Jews, likely a result of indirect gene flow. Within an African and Eurasian context, the distribution of alleles of a variable T(n) repeat, and the spread of haplotypes containing Africa-specific alleles, provide evidence of a genetic continuity from Sub-Saharan Africa to the Near East, and furthermore suggest that a bottleneck occurred in Ethiopia associated with an out of Africa expansion. Ethiopian genetic heterogeneity, as evidenced by principal component analysis of haplotype frequencies, most likely resulted from periods of subsequent admixture. While these results are from the analysis of one locus, we feel that in association with data from other marker systems they add a complementary perspective on the history of Ethiopia.

Africa↗
PubMed2005

The genetics of the pre-Roman Iberian Peninsula: a mtDNA study of ancient Iberians.

The Iberians developed a surprisingly sophisticated culture in the Mediterranean coast of the Iberian Peninsula from the 6th century BC until their conquest by the Romans in the 2nd century BC. They spoke and wrote a non-Indo-European language that still cannot be understood; their origins and relationships with other non-Indo-European peoples, like the Etruscans, are unclear, since their funerary practices were based on the cremation of bodies, and therefore anthropology has been unable to approach the study of this people. We have retrieved mitochondrial DNA (mtDNA) from a few of the scarce skeletal remains that have been preserved, some of them belonging to ritualistically executed individuals. The most stringent authentication criteria proposed for ancient DNA, such as independent replication, amino-acid analysis, quantitation of template molecules, multiple extractions and cloning of PCR products, have been followed to obtain reliable sequences from the mtDNA hypervariable region 1 (HVR1), as well as some haplogroup diagnostic SNPs. Phylogeographic analyses show that the haplogroup composition of the ancient Iberians was very similar to that found in modern Iberian Peninsula populations, suggesting a long-term genetic continuity since pre-Roman times. Nonetheless, there is less genetic diversity in the ancient Iberians than is found among modern populations, a fact that could reflect the small population size at the origin of the population sampled, and the heterogenic tribal structure of the Iberian society. Moreover, the Iberians were not especially closely related to the Etruscans, which points to considerable genetic heterogeneity in Pre-Roman Western Europe.

Adult↗
PubMed2005

A novel Gypsy founder mutation, p.Arg1109X in the CMT4C gene, causes variable peripheral neuropathy phenotypes.

BACKGROUND: Linkage, haplotype and sequencing analysis in a large Spanish Gypsy kindred with multiple members affected by autosomal recessive peripheral neuropathy led to the identification of a novel mutation, p.Arg1109X, in the CMT4C gene. The screening of further unrelated patients, and of a panel of ethnically matched controls, showed that p.Arg1109X is an ancestral mutation which occurs in Gypsy populations across Europe and is the most common cause of autosomal recessive Charcot-Marie-Tooth disease in Spanish Gypsies. OBJECTIVE: To report the identification of a novel Gypsy founder mutation causing autosomal recessive CMT4C disease in a sample of homozygous affected individuals. RESULTS: The mutation was associated with a surprisingly broad spectrum of neuropathy phenotypes, with variation in the age at onset, rate of progression, severity of muscle and sensory involvement, the presence of scoliosis, and cranial nerve involvement. CONCLUSIONS: Ascertainment and further studies of CMT4C patients in this population will provide a unique opportunity for characterising the full range of clinical manifestations of the disease in a genetically homogeneous sample.

Arginine↗
PubMed2004

Unravelling migrations in the steppe: mitochondrial DNA sequences from ancient central Asians.

This study helps to clarify the debate on the Western and Eastern genetic influences in Central Asia. Thirty-six skeletal remains from Kazakhstan (Central Asia), excavated from different sites dating between the fifteenth century BC to the fifth century AD, have been analysed for the hypervariable control region (HVR-I) and haplogroup diagnostic single nucleotide polymorphisms (SNPs) of the mitochondrial DNA genome. Standard authentication criteria for ancient DNA studies, including multiple extractions, cloning of PCR products and independent replication, have been followed. The distribution of east and west Eurasian lineages through time in the region is concordant with the available archaeological information: prior to the thirteenth-seventh century BC, all Kazakh samples belong to European lineages; while later an arrival of east Eurasian sequences that coexisted with the previous west Eurasian genetic substratum can be detected. The presence of an ancient genetic substratum of European origin in West Asia may be related to the discovery of ancient mummies with European features in Xinjiang and to the existence of an extinct Indo-European language, Tocharian. This study demonstrates the usefulness of the ancient DNA in unravelling complex patterns of past human migrations so as to help decipher the origin of present-day admixed populations.

DNA Primers↗
PubMed2004

Variation of the prion gene in chimpanzees and its implication for prion diseases.

In humans, familial prion diseases are linked to mutations in the PRNP gene. We have sequenced part of this gene in a large sample of common chimpanzee, Pan troglodytes (n=130 chromosomes). No variation in codons 129 and 219 has been observed: all chimpanzees were homozygous for the Met allele, which in humans increases susceptibility to Creutzfeldt-Jakob disease. We found two sequence variants: one is a synonymous polymorphism unique to the chimpanzee at codon 226, TAC to TAT (Y), with a TAC allele frequency of 80.6%; the other is a non-synonymous change at codon 148 (R148H) that falls in the target epitope for some common commercial antibodies used for prion diagnostics, and is highly conserved across species. The pathogenicity of this mutation is still unknown.

Amino Acid Sequence↗
PubMed2004

Alu insertion polymorphisms in the Balkans and the origins of the Aromuns.

We have analysed 11 human-specific Alu insertion polymorphisms in the Balkans to elucidate the origins of the Aromuns, a linguistic isolate inhabiting scattered areas in the Balkan Peninsula. Four Aromun samples (two from the Republic of Macedonia, one from Albania, and one from Romania) and five neighbouring populations (Macedonians, Albanians, Romanians, Greeks, and Turks) were analysed by means of genetic distances, principal components and analyses of the molecular variance (AMOVA). Three hypotheses were tested: Aromuns are Romanophonic Greeks; the result of a Romanian southward migration; or local descendants of the Thracians. The analyses show that the Aromuns do not constitute a homogeneous group separated from the rest of the Balkan populations. Grouping by language or geography does not explain the genetic differences observed in the region, suggesting a lack of genetic structure in the area. Aromuns do not seem to be particularly related to Greeks, Romanians, or to other Romance speakers. The Aromuns might have their origin to the south of the Danube river, with extensive gene flow with the neighbouring populations. The present results suggest a common ancestry of all Balkan populations, including Aromuns, with a lack of correlation between genetic differentiation and language or ethnicity, stressing that no major migration barriers have existed in the making of the complex Balkan human puzzle.

Alu Elements↗
PubMed2003

Understanding the dynamics of Spinocerebellar Ataxia 8 (SCA8) locus through a comparative genetic approach in humans and apes.

Spinocerebellar Ataxia 8 (SCA8) is a neurodegenerative disorder caused by expansion of a trinucleotide repeat. We undertake a comparative genetic analysis among human populations and primate species in the normal variation range, where forces that shaped present diversity can be recognised. We determinate number of repeats of the short tandem repeat through allele length sizing and sequencing methods. Human allele distributions are very similar among populations, ruling out ethnicity as a genetic risk for allele expansion. Primate comparison shows human-specific features, with longer human alleles due to a novel variable trinucleotide repeat, not present in non-human primates, which increased the disease-causing expansion likelihood. SCA8 seems to be a human specific disease.

Alanine↗
PubMed2003

Mitochondrial DNA from pre-Columbian Ciboneys from Cuba and the prehistoric colonization of the Caribbean.

To assess the genetic affinities of extinct Ciboneys (also called Guanajuatabeys) from Cuba, 47 pre-Columbian skeletal samples belonging to this group were analyzed using ancient DNA techniques. At the time of European contact, the center and east of Cuba were occupied by agriculturalist Taino groups, while the west was mainly inhabited by Ciboneys, hunter-gatherers who have traditionally been considered a relic population descending from the initial colonization of the Caribbean. The mtDNA hypervariable region I (HVR-I) and haplogroup-specific markers were amplified and sequenced in 15 specimens using overlapping fragments; amplification from second extractions from the same sample, independent replication in different laboratories, and cloning of some PCR products support the authenticity of the sequences. Three of the five major mtDNA Amerindian lineages (A, C, and D) are present in the sample analyzed, in frequencies of 0.07, 0.60, and 0.33, respectively. Different phylogenetic analyses seem to suggest that the Caribbean most likely was populated from South America, although the data are still inconclusive, and Central American influences cannot be discarded. Our hypothesis is that the colonization of the Caribbean mainly took place in successive migration movements that emanated from the same area in South America, around the Lower Orinoco Valley: the first wave consisted of hunter-gatherer groups (ancestors of the Ciboneys), a subsequent wave of agriculturalists (ancestors of the Tainos), and a latter one of nomadic Carib warriors. However, further genetic studies are needed to confirm this scenario.

Bone and Bones↗
PubMed2003

Possible increased risk for Alzheimer's disease associated with neprilysin gene.

Neprilysin has recently been reported to be the major physiological Abeta-degradating enzyme. In this study we describe a new biallelic polymorphism in the 3'UTR of the neprilysin gene in a representative population sample. The (*)159C/C genotype was found to be associated with an increased risk for Alzheimer's disease in an age-dependent manner. Adjusting for sex and APOE status, an odds ratio of 2.74 (p < 0.05) was observed among patients under 75 years old.

3' Untranslated Regions↗
PubMed2003

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

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

Alleles↗
PubMed2003

Joining the pillars of Hercules: mtDNA sequences show multidirectional gene flow in the western Mediterranean.

Phylogenetic analysis of mitochondrial DNA (mtDNA) performed in Western Mediterranean populations has shown that both shores share a common set of mtDNA haplogroups already found in Europe and the Middle East. Principal co-ordinates of genetic distances and principal components analyses based on the haplotype frequencies show that the main genetic difference is attributed to the higher frequency of sub-Saharan L haplogroups in NW Africa, showing some gene flow across the Sahara desert, with a major impact in the southern populations of NW Africa. The AMOVA demonstrates that SW European populations are highly homogeneous whereas NW African populations display a more heterogeneous genetic pattern, due to an east-west differentiation as a result of gene flow coming from the East. Despite the shared haplogroups found in both areas, the European V and the NW African U6 haplogroups reveal the traces of the Mediterranean Sea permeability to female migrations, and allowed for determination and quantification of the genetic contribution of both shores to the genetic landscape of the geographic area. Comparison of mtDNA data with autosomal markers and Y-chromosome lineages, analysed in the same populations, shows a congruent pattern, although female-mediated gene flow seems to have been more intense than male-mediated gene flow.

Analysis of Variance↗
PubMed2001

High-resolution analysis of human Y-chromosome variation shows a sharp discontinuity and limited gene flow between northwestern Africa and the Iberian Peninsula.

In the present study we have analyzed 44 Y-chromosome biallelic polymorphisms in population samples from northwestern (NW) Africa and the Iberian Peninsula, which allowed us to place each chromosome unequivocally in a phylogenetic tree based on >150 polymorphisms. The most striking results are that contemporary NW African and Iberian populations were found to have originated from distinctly different patrilineages and that the Strait of Gibraltar seems to have acted as a strong (although not complete) barrier to gene flow. In NW African populations, an Upper Paleolithic colonization that probably had its origin in eastern Africa contributed 75% of the current gene pool. In comparison, approximately 78% of contemporary Iberian Y chromosomes originated in an Upper Paleolithic expansion from western Asia, along the northern rim of the Mediterranean basin. Smaller contributions to these gene pools (constituting 13% of Y chromosomes in NW Africa and 10% of Y chromosomes in Iberia) came from the Middle East during the Neolithic and, during subsequent gene flow, from Sub-Saharan to NW Africa. Finally, bidirectional gene flow across the Strait of Gibraltar has been detected: the genetic contribution of European Y chromosomes to the NW African gene pool is estimated at 4%, and NW African populations may have contributed 7% of Iberian Y chromosomes. The Islamic rule of Spain, which began in a.d. 711 and lasted almost 8 centuries, left only a minor contribution to the current Iberian Y-chromosome pool. The high-resolution analysis of the Y chromosome allows us to separate successive migratory components and to precisely quantify each historical layer.

Africa South of the Sahara↗
PubMed2001

Glucocerebrosidase pseudogene variation and Gaucher disease: Recognizing pseudogene tracts in GBA alleles.

We surveyed the genetic variability of the glucocerebrosidase pseudogene (psGBA) in a worldwide sample of 100 human chromosomes. psGBA is the non-functional duplicate of the gene responsible for Gaucher disease (GBA), the most common lipid storage disorder. The existence of only one psGBA allele described until now, together with the high homology between GBA and psGBA, often prevented recognition of the complex alleles formed by the combination of GBA and psGBA, because psGBA variants could be confused with GBA mutations. In order to determine the variability existent in psGBA, the whole psGBA DNA segment was PCR-amplified and sequenced, and the genotype for all samples was obtained. The ascertainment of the phase among the heterozygous sites was possible through cloning and sequencing a single allele. Eighteen variable sites were detected along psGBA. Two of the variants already have been reported as Gaucher-causing mutations when present in GBA alleles. The other variants were unknown. The knowledge of the psGBA variants described in this report will allow identification of psGBA-GBA complex alleles that may aid in understanding the intricate phenotype-genotype relationship in Gaucher disease.

Alleles↗
PubMed2001

Profiles of accepted mutation: from neutrality in a pseudogene to disease-causing mutation on its homologous gene.

We have compared the substitution pattern of the glucocerebrosidase gene (GBA) and the glucocerebrosidase pseudogene (psGBA), two highly homologous regions under different selective pressures and within the same genomic background. Mutations in GBA may lead to Gaucher disease, an inborn metabolic disorder. Disease-causing mutations and neutral variation in the gene have been compared to neutral variation in the pseudogene. This comparison offers a unique opportunity to better understand the action of purifying selection, since the differences between mutational patterns can be attributed to different selective pressures. A similar frequency of CpG dinucleotides was observed in GBA and in psGBA, and CpG pairs were mutated with the same high frequency in both regions. However, nucleotides not in CpG pairs were more likely to contribute to disease-causing mutation than to accepted polymorphisms. This pattern, which resulted in a lower transition to transversion ratio in the gene, may be due to CpG avoidance on critical regions within exons.

Base Composition↗
PubMed2001

MtDNA from extinct Tainos and the peopling of the Caribbean.

Tainos and Caribs were the inhabitants of the Caribbean when Columbus reached the Americas; both human groups became extinct soon after contact, decimated by the Spaniards and the diseases they brought. Samples belonging to pre-Columbian Taino Indians from the La Caleta site (Dominican Republic) have been analyzed, in order to ascertain the genetic affinities of these groups in relation to present-day Amerinds, and to reconstruct the genetic and demographic events that took place during the peopling of the Caribbean. Twenty-seven bone samples were extracted and analyzed for mtDNA variation. The four major Amerindian mtDNA lineages were screened through amplification of the specific marker regions and restriction enzymatic digestion, when needed. The HVRI of the control region was amplified with four sets of overlapping primers and sequenced in 19 of the samples. Both restriction enzyme and sequencing results suggest that only two (C and D) of the major mtDNA lineages were present in the sample: 18 individuals (75%) belonged to the C haplogroup, and 6 (25%) to the D haplogroup. Sequences display specific substitutions that are known to correlate with each haplogroup, a fact that helped to reject the possibility of European DNA contamination. A low rate of Taq misincorporations due to template damage was estimated from the cloning and sequencing of different PCR products of one of the samples. High frequencies of C and D haplogroups are more common in South American populations, a fact that points to that sub-continent as the homeland of the Taino ancestors, as previously suggested by linguistic and archaeological evidence. Sequence and haplogroup data show that the Tainos had a substantially reduced mtDNA diversity, which is indicative of an important founder effect during the colonization of the Caribbean Islands, assumed to have been a linear migratory movement from mainland South America following the chain configuration of the Antilles.

Asian People↗