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Xavier Estivill

Publications and source records attributed to Xavier Estivill.

At least 19 recordsLinked to original sources
PubMed2007

Inter-population variability of DEFA3 gene absence: correlation with haplotype structure and population variability.

BACKGROUND: Copy number variants (CNVs) account for a significant proportion of normal phenotypic variation and may have an important role in human pathological variation. The alpha-defensin cluster on human chromosome 8p23.1 is one of the better-characterized CNVs, in which high copy number variability affecting the DEFA1 and DEFA3 genes has been reported. Moreover, the DEFA3 gene has been found to be absent in a significant proportion of control population subjects. CNVs involving immune genes, such as alpha-defensins, are possibly contributing to innate immunity differences observed between individuals and influence predisposition and susceptibility to disease. RESULTS: We have tested the DEFA3 absence in 697 samples from different human populations. The proportion of subjects lacking DEFA3 has been found to vary from 10% to 37%, depending on the population tested, suggesting differences in innate immune function between populations. Absence of DEFA3 was correlated with the region's haplotype block structure. African samples showed a higher intra-populational variability together with the highest proportion of subjects without DEFA3 (37%). Association analysis of DEFA3 absence with 136 SNPs from a 100-kb region identified a conserved haplotype in the Caucasian population, extending for the whole region. CONCLUSION: Complexity and variability are essential genomic features of the alpha-defensin cluster at the 8p23.1 region. The identification of population differences in subjects lacking the DEFA3 gene may be suggestive of population-specific selective pressures with potential impact on human health.

Asian People↗
PubMed2007

Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia.

BACKGROUND: There is an increasing recognition that the pathophysiology of mental disorders could be the result of deregulation of synaptic plasticity with alterations of neurotrophins. The valine (Val)66-to-methionine (Met) variant, located in the pro brain-derived neurotrophic factor (BDNF) sequence, has been extensively studied through linkage and association approaches in several psychiatric disorders. METHODS: We performed a meta-analysis restricted to individual case-control studies in different categories of mental disorders and BDNF Val66Met polymorphism. We included data from 39 case-control studies encompassing psychiatric phenotypes: eating disorders, substance-related disorders, mood disorders, and schizophrenia, among others. RESULTS: The association of Val66Met was confined to three diagnoses: substance-related disorders, eating disorders, and schizophrenia. The Val/Met and the Met/Met genotypes increase the risk for eating disorders up to 33%, while these same genotypes confer a 21% protective effect in substance-related disorders. The homozygous carriers Met/Met showed a 19% increased risk of schizophrenia with respect to the heterozygous state. CONCLUSIONS: The study confirms the association of Val66Met to substance-related disorders, eating disorders, and schizophrenia. It remains to be determined if other variants in tight linkage disequilibrium with Val66Met could configure an extended functional haplotype that would explain observed discrepancies in risk estimations across studies.

Adult↗
PubMed2007

Molecular characterization of a t(9;12)(p21;q13) balanced chromosome translocation in combination with integrative genomics analysis identifies C9orf14 as a candidate tumor-suppressor.

A large number of nevi (LNN) is a high risk phenotypic trait for developing cutaneous malignant melanoma (CMM). In this study, the breakpoints of a t(9;12)(p21;q13) balanced chromosome translocation were finely mapped in a family with LNN and CMM. Molecular characterization of the 9p21 breakpoint identified a novel gene C9orf14 expressed in melanocytes disrupted by the translocation. Integrative analysis of functional genomics data was applied to determine the role of C9orf14 in CMM development. An analysis of genome-wide DNA copy number alterations in melanoma tumors revealed the loss of the C9orf14 locus, located proximal to CDKN2A, in approximately one-fourth of tumors. Analysis of gene expression data in cancer cell lines and melanoma tumors suggests a loss of C9orf14 expression in melanoma tumorigenesis. Taken together, our results indicate that C9orf14 is a candidate tumor-suppressor for nevus development and late stage melanoma at 9p21, a region frequently deleted in different types of human cancers.

Chromosomes, Human, Pair 12↗
PubMed2006

Global variation in copy number in the human genome.

Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.

Chromosome Mapping↗
PubMed2006

Genome assembly comparison identifies structural variants in the human genome.

Numerous types of DNA variation exist, ranging from SNPs to larger structural alterations such as copy number variants (CNVs) and inversions. Alignment of DNA sequence from different sources has been used to identify SNPs and intermediate-sized variants (ISVs). However, only a small proportion of total heterogeneity is characterized, and little is known of the characteristics of most smaller-sized (<50 kb) variants. Here we show that genome assembly comparison is a robust approach for identification of all classes of genetic variation. Through comparison of two human assemblies (Celera's R27c compilation and the Build 35 reference sequence), we identified megabases of sequence (in the form of 13,534 putative non-SNP events) that were absent, inverted or polymorphic in one assembly. Database comparison and laboratory experimentation further demonstrated overlap or validation for 240 variable regions and confirmed >1.5 million SNPs. Some differences were simple insertions and deletions, but in regions containing CNVs, segmental duplication and repetitive DNA, they were more complex. Our results uncover substantial undescribed variation in humans, highlighting the need for comprehensive annotation strategies to fully interpret genome scanning and personalized sequencing projects.

Base Sequence↗
PubMed2006

Contribution of the serotoninergic system to anxious and depressive traits that may be partially responsible for the phenotypical variability of bulimia nervosa.

Eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), are complex psychiatric phenotypes influenced by both genetic and environmental factors. We investigated the genetic contribution of four single nucleotide polymorphisms (SNPs) within the serotonin receptor 5HT2C and two sequence variants within the serotonin transporter SLC6A4 to different ED-related psychopathological symptoms in a total sample of 82 ED patients. All patients were diagnosed according to DSM-IV criteria and underwent diagnostic and psychopathological assessments by means of structured clinical interviews and rating scales. We detected significant evidence of association between the -995A/-759T/-697C/Cys23 haplotype of the 5HT2C gene and different anxious and depressive subscales of the SCL90-R instrument, that included Somatization (p = 0.029), Obsessive-Compulsiveness (p = 0.021), Depression (p = 0.032), Anxiety (p = 0.004), Hostility (p = 0.028), Phobic Anxiety (p = 0.029) and Paranoid Ideation (p = 0.008), in BN patients. We also observed a strong association between the 5HTTLPR polymorphism of the SLC6A4 gene and Anxiety in the same group of BN patients (p = 0.004). However, no epistatic effects between the 5HT2C and SLC6A4 genes on the different anxious and depressive subscales were observed. Our preliminary data suggest that the serotoninergic system contributes to the different psychopathological symptoms that may be partially responsible for the phenotypical variability within the bulimic phenotype.

Adult↗
PubMed2006

Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction.

Accumulating evidence has suggested that neurotrophins participate in the pathophysiology of mood disorders. We have developed transgenic mice overexpressing the full-length neurotrophin-3 receptor TrkC (TgNTRK3) in the central nervous system. TgNTRK3 mice show increased anxiety-like behavior and enhancement of panic reaction in the mouse defense test battery, along with an increase in the number and density of catecholaminergic (tyrosine hydroxylase positive) neurons in locus coeruleus and substantia nigra. Furthermore, treatment of TgNTRK3 mice with diazepam significantly attenuated the anxiety-like behaviors in the plus maze. These results provide evidence for the involvement of TrkC in the development of noradrenergic neurons in the central nervous system with consequences on anxiety-like behavior and panic reaction. Thus, changes in TrkC expression levels could contribute to the phenotypic expression of panic disorder through a trophic effect on noradrenergic neurons in the locus coeruleus. Our results demonstrate that the elevated NT3-TrkC tone via overexpression of TrkC in the brain may constitute a molecular mechanism for the expression of anxiety and anxiety.

Animals↗
PubMed2006

Cooperation to amplify gene-dosage-imbalance effects.

Trisomy 21, also known as Down syndrome (DS), is a complex developmental disorder that affects many organs, including the brain, heart, skeleton and immune system. A working hypothesis for understanding the consequences of trisomy 21 is that the overexpression of certain genes on chromosome 21, alone or in cooperation, is responsible for the clinical features of DS. There is now compelling evidence that the protein products of two genes on chromosome 21, Down syndrome candidate region 1 (DSCR1) and dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), interact functionally, and that their increased dosage cooperatively leads to dysregulation of the signaling pathways that are controlled by the nuclear factor of activated T cells (NFAT) family of transcription factors, with potential consequences for several organs and systems that are affected in DS individuals.

DNA-Binding Proteins↗
PubMed2006

Complex patterns of copy number variation at sites of segmental duplications: an important category of structural variation in the human genome.

The structural diversity of the human genome is much higher than previously assumed although its full extent remains unknown. To investigate the association between segmental duplications that display constitutive copy number differences (CNDs) between humans and the great apes and those which exhibit polymorphic copy number variations (CNVs) between humans, we analysed a BAC array enriched with segmental duplications displaying such CNDs. This study documents for the first time that in addition to human-specific gains common to all humans, these duplication clusters (DCs) also exhibit polymorphic CNVs > 40 kb. Segmental duplication is known to have been a frequent event during human genome evolution. Importantly, among the CNV-associated genes identified here, those involved in transcriptional regulation were found to be significantly overrepresented. Complex patterns of variation were evident at sites of DCs, manifesting as inter-individual differentially sized copy number alterations at the same genomic loci. Thus, CNVs associated with segmental duplications do not simply represent insertion/deletion polymorphisms, but rather constitute a wide variety of rearrangements involving differential amplification and partial gains and losses with high inter-individual variability. Although the number of CNVs was not found to differ between Africans and Caucasians/Asians, the average number of variant patterns per locus was significantly lower in Africans. Thus, complex variation patterns characterizing segmental duplications result from relatively recent genomic rearrangements. The high number of these rearrangements, some of which are potentially recurrent, together with differences in population size and expansion dynamics, may account for the greater diversity of CNV in Caucasians/Asians as compared with Africans.

Animals↗
PubMed2006

Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations.

The human mitochondrial 12S ribosomal RNA (rRNA) A1555G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation revealed that the A1555G mutation is a primary factor underlying the development of deafness but is not sufficient to produce a deafness phenotype. However, it has been proposed that nuclear-modifier genes modulate the phenotypic manifestation of the A1555G mutation. Here, we identified the nuclear-modifier gene TRMU, which encodes a highly conserved mitochondrial protein related to transfer RNA (tRNA) modification. Genotyping analysis of TRMU in 613 subjects from 1 Arab-Israeli kindred, 210 European (Italian pedigrees and Spanish pedigrees) families, and 31 Chinese pedigrees carrying the A1555G or the C1494T mutation revealed a missense mutation (G28T) altering an invariant amino acid residue (A10S) in the evolutionarily conserved N-terminal region of the TRMU protein. Interestingly, all 18 Arab-Israeli/Italian-Spanish matrilineal relatives carrying both the TRMU A10S and 12S rRNA A1555G mutations exhibited prelingual profound deafness. Functional analysis showed that this mutation did not affect importation of TRMU precursors into mitochondria. However, the homozygous A10S mutation leads to a marked failure in mitochondrial tRNA metabolisms, specifically reducing the steady-state levels of mitochondrial tRNA. As a consequence, these defects contribute to the impairment of mitochondrial-protein synthesis. Resultant biochemical defects aggravate the mitochondrial dysfunction associated with the A1555G mutation, exceeding the threshold for expressing the deafness phenotype. These findings indicate that the mutated TRMU, acting as a modifier factor, modulates the phenotypic manifestation of the deafness-associated 12S rRNA mutations.

Amino Acid Sequence↗
PubMed2006

Cochlear alterations in deaf and unaffected subjects carrying the deafness-associated A1555G mutation in the mitochondrial 12S rRNA gene.

The A1555G mutation in the mitochondrial small ribosomal RNA gene (12S rRNA) has been associated with aminoglycoside-induced, nonsyndromic hearing loss. However, the clinical phenotype of A1555G carriers is extremely variable. In the present study, we have performed an audiological evaluation of a group of deaf patients and hearing carriers of mutation A1555G with the aim to assess the prevalence of the mutation and determine the associated cochlear alterations. Fifty-four patients affected of nonsyndromic hearing loss were screened for the presence of the A1555G mitochondrial mutation. Nine of the familial cases (21%) carried the A1555G mutation, whereas the mutation was not found in any of the sporadic cases. The positive cases and some of their family members underwent a clinical study consisting in a clinical evaluation and audiological testing. The phenotype of A1555G patients varied in age of onset and severity of hearing loss, ranging from profound deafness to completely normal hearing. The audiometric alterations showed bilateral hearing loss, being more severe at high frequencies. Otoacoustic emissions were absent in deaf A1555G carriers, and auditory brainstem response indicated a prolonged Wave I, suggesting a cochlear dysfunction without any effect of the auditory nerve. Moreover, all hearing carriers of A1555G also presented alterations in cochlear physiology. In conclusion, the A1555G mitochondrial mutation causes a cochlear form of deafness, characterized by a more severe loss of hearing at high frequencies. Although the expression of the mutation is variable, cochlear alterations are present in all carriers of mutation A1555G.

Adult↗
PubMed2006

Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations.

Nuclear modifier genes have been proposed to modulate the phenotypic manifestation of human mitochondrial 12S rRNA A1491G mutation associated with deafness in many families world-wide. Here we identified and characterized the putative nuclear modifier gene TRMU encoding a highly conserved mitochondrial protein related to tRNA modification. A 1937bp TRMU cDNA has been isolated and the genomic organization of TRMU has been elucidated. The human TRMU gene containing 11 exons encodes a 421 residue protein with a strong homology to the TRMU-like proteins of bacteria and other homologs. TRMU is ubiquitously expressed in various tissues, but abundantly in tissues with high metabolic rates including heart, liver, kidney, and brain. Immunofluorescence analysis of human 143B cells expressing TRMU-GFP fusion protein demonstrated that the human Trmu localizes and functions in mitochondrion. Furthermore, we show that in families with the deafness-associated 12S rRNA A1491G mutation there is highly suggestive linkage and linkage disequilibrium between microsatellite markers adjacent to TRMU and the presence of deafness. These observations suggest that human TRMU may modulate the phenotypic manifestation of the deafness-associated mitochondrial 12S rRNA mutations.

Base Sequence↗
PubMed2006

Mitochondrial 12S rRNA gene mutations affect RNA secondary structure and lead to variable penetrance in hearing impairment.

Mutations in the mitochondrial DNA are one of the most important causes of sensorineural hearing loss, especially in the 12S ribosomal RNA (rRNA) gene. We have analyzed the mtDNA 12S rRNA gene in a cohort of 443 families with hearing impairment, and have identified the A1555G mutation in 69 unrelated cases. A1555G is not a fully penetrant change, since only 63% of subjects with this change have developed hearing impairment. In addition, only 22% of the 183 A1555G deaf subjects were treated with aminoglycosides. Two novel nucleotide changes (T1291C and T1243C) were identified. T1243C was found in five deafness cases and one control sample. Mutation T1291C was detected in all maternally related individuals of a pedigree and in none of 95 control samples. Conservation analysis and comparison of the 12S rRNA structure with the 16S rRNA of Escherichia coli showed that the T at nucleotide 1243 and A at nucleotide 1555 are conserved positions. Prediction of RNA secondary structure showed changes in all 12S rRNA variants, the most severe being for T1291C. The reported data confirm the high prevalence of mutation A1555G in deafness cases and the major role of the 12S rRNA gene in hearing. The two novel changes reported here might have different contributions as deafness-related variants. T1291C fulfills the criteria of a disease-causing change. As in the case of mutation A1555G, the underlying phenotype of T1291C is not homogeneous for all family members, providing evidence for the implication of environmental and/or additional genetic factors.

Adult↗
PubMed2006

Identification of large-scale human-specific copy number differences by inter-species array comparative genomic hybridization.

Copy number differences (CNDs), and the concomitant differences in gene number, have contributed significantly to the genomic divergence between humans and other primates. To assess its relative importance, the genomes of human, common chimpanzee, bonobo, gorilla, orangutan and macaque were compared by comparative genomic hybridization using a high-resolution human BAC array (aCGH). In an attempt to avoid potential interference from frequent intra-species polymorphism, pooled DNA samples were used from each species. A total of 322 sites of large-scale inter-species CND were identified. Most CNDs were lineage-specific but frequencies differed considerably between the lineages; the highest CND frequency among hominoids was observed in gorilla. The conserved nature of the orangutan genome has already been noted by karyotypic studies and our findings suggest that this degree of conservation may extend to the sub-microscopic level. Of the 322 CND sites identified, 14 human lineage-specific gains were observed. Most of these human-specific copy number gains span regions previously identified as segmental duplications (SDs) and our study demonstrates that SDs are major sites of CND between the genomes of humans and other primates. Four of the human-specific CNDs detected by aCGH map close to the breakpoints of human-specific karyotypic changes [e.g., the human-specific inversion of chromosome 1 and the polymorphic inversion inv(2)(p11.2q13)], suggesting that human-specific duplications may have predisposed to chromosomal rearrangement. The association of human-specific copy number gains with chromosomal breakpoints emphasizes their potential importance in mediating karyotypic evolution as well as in promoting human genomic diversity.

Animals↗
PubMed2006

A recessive Mendelian model to predict carrier probabilities of DFNB1 for nonsyndromic deafness.

Mutations in the DFNB1 locus, where two connexin genes are located (GJB2 and GJB6), account for half of congenital cases of nonsyndromic autosomal recessive deafness. Because of the high frequency of DFNB1 gene mutations and the availability of genetic diagnostic tests involving these genes, they are the best candidates to develop a risk prediction model of being hearing impaired. People undergoing genetic counseling are normally interested in knowing the probability of having a hearing impaired child given his/her family history. To address this, a Mendelian model that predicts the probability of being a carrier of DFNB1 mutations, using family history of deafness, has been developed. This probability will be useful as additional information to decide whether or not a genetic test should be performed. This model incorporates Mendelian mode of inheritance, the age of onset of the disease, and the current age of hearing family members. The carrier probabilities are obtained using Bayes' theorem, in which mutation prevalence is used as the prior distribution. We have validated our model by using information from 305 families affected with congenital or progressive nonsyndromic deafness, in which genetic analysis of GJB2 and GJB6 had already been performed. This model works well, especially in homozygous carriers, showing a high discriminative power. This indicates that our proposed model can be useful in the context of clinical counseling of autosomal recessive disorders.

Adult↗
PubMed2005

Murine segmental duplications are hot spots for chromosome and gene evolution.

Mouse and rat genomic sequences permit us to obtain a global view of evolutionary rearrangements that have occurred between the two species and to define hallmarks that might underlie these events. We present a comparative study of the sequence assemblies of mouse and rat genomes and report an enrichment of rodent-specific segmental duplications in regions where synteny is not preserved. We show that segmental duplications present higher rates of molecular evolution and that genes in rearranged regions have evolved faster than those located elsewhere. Previous studies have shown that synteny breakpoints between the mouse and the human genomes are enriched in human segmental duplications, suggesting a causative connection between such structures and evolutionary rearrangements. Our work provides further evidence to support the role of segmental duplications in chromosomal rearrangements in the evolution of the architecture of mammalian chromosomes and in the speciation processes that separate the mouse and the rat.

Animals↗