Stylianos E Antonarakis

University of Geneva, Genève, Geneva, Switzerland

Are you Stylianos E Antonarakis?

Claim your profile

Publications (734)6092.06 Total impact

  • Source
    Seizure 07/2015; DOI:10.1016/j.seizure.2015.06.015 · 2.06 Impact Factor
  • Source
    PLoS ONE 05/2015; 10(5). DOI:10.1371/journal.pone.0126475 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Spontaneously arising mouse mutations have served as the foundation for understanding gene function for over 100 years. We have used exome sequencing in an effort to identify the causative mutations for 172 distinct, spontaneously arising mouse models of Mendelian disorders, including a broad range of clinically relevant phenotypes. To analyze the resulting data, we developed an analytics pipeline that is optimized for mouse exome data and a variation database that allows for reproducible, user-defined data mining as well as nomination of mutation candidates through knowledge-based integration of sample and variant data. Using these new tools, putative pathogenic mutations were identified for 91 (53%) of the strains in our study. Despite the increased power offered by potentially unlimited pedigrees and controlled breeding, about half of our exome cases remained unsolved. Using a combination of manual analyses of exome alignments and whole genome sequencing, we provide evidence that a large fraction of unsolved exome cases have underlying structural mutations. This result directly informs efforts to investigate the similar proportion of apparently Mendelian human phenotypes that are recalcitrant to exome sequencing. Published by Cold Spring Harbor Laboratory Press.
    Genome Research 04/2015; DOI:10.1101/gr.186882.114 · 13.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The trisomy of human chromosome 21 (Hsa21), which causes Down syndrome (DS), is the most common viable human aneuploidy. In contrast to trisomy, the complete monosomy (M21) of Hsa21 is lethal, and only partial monosomy or mosaic monosomy of Hsa21 is seen. Both conditions lead to variable physiological abnormalities with constant intellectual disability, locomotor deficits, and altered muscle tone. To search for dosage-sensitive genes involved in DS and M21 phenotypes, we created two new mouse models: the Ts3Yah carrying a tandem duplication and the Ms3Yah carrying a deletion of the Hspa13-App interval syntenic with 21q11.2-q21.3. Here we report that the trisomy and the monoso-my of this region alter locomotion, muscle strength, mass, and energetic balance. The expression profiling of skeletal muscles revealed global changes in the regulation of genes implicated in energetic metabolism, mitochondrial activity, and biogenesis. These genes are downregulated in Ts3Yah mice and upregulated in Ms3Yah mice. The shift in skeletal muscle metabolism correlates with a change in mitochondrial proliferation without an alteration in the respiratory function. However, the reactive oxygen species (ROS) production from mitochondrial complex I decreased in Ms3Yah mice, while the membrane permeability of Ts3Yah mitochondria slightly increased. Thus, we demonstrated how the Hspa13-App interval controls metabolic and mitochondrial phenotypes in muscles certainly as a consequence of change in dose of Gabpa, Nrip1, and Atp5j. Our results indicate that the copy
    PLoS Genetics 03/2015; · 8.17 Impact Factor
  • European Psychiatry 03/2015; 30:1421. DOI:10.1016/S0924-9338(15)31098-1 · 3.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chromosomal rearrangements with duplication of the lamin B1 gene (LMNB1) underlie autosomal dominant adult-onset leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive CNS demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (∼660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.
    Human Molecular Genetics 02/2015; · 6.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chromosomal rearrangements with duplication of the lamin B1 gene (LMNB1) underlie autosomal dominant adult-onset leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive CNS demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (∼660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes. © The Author 2015. Published by Oxford University Press.
    Human Molecular Genetics 02/2015; 24(11). DOI:10.1093/hmg/ddv065 · 6.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modelling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a unique genetic system for investigation of pathological and protective mechanisms for accelerated ageing, neurodegeneration, dementia, cancer and other important common diseases. New drugs could be identified and disease mechanisms better understood by establishment of well controlled cell model systems. We have developed a first non-integration-reprogrammed isogenic human induced-pluripotent-stem-cells (iPSC) model of DS by reprogramming the skin fibroblasts from an adult individual with constitutional mosaicism for DS, and separately cloned multiple isogenic T21 and euploid (D21) iPSC lines. Our model shows a very low number of reprogramming rearrangements as assessed by a high-resolution whole genome CGH-array hybridisation and it reproduces several cellular pathologies seen in primary human DS cells, as assessed by automated high-content microscopic analysis. Early differentiation shows an imbalance of the lineage-specific stem/progenitor cell compartments: T21 causes slower proliferation of neural and faster expansion of hematopoietic lineage. T21 iPSC-derived neurons show increased production of amyloid peptide-containing material, a decrease in mitochondrial membrane potential, and an increased number and abnormal appearance of mitochondria. Finally, T21-derived neurons show significantly higher number of DNA double-strand breaks than isogenic D21 controls. Our fully isogenic system therefore opens possibilities for modelling mechanisms of developmental, accelerated ageing, and neurodegenerative pathologies caused by T21. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
    Stem Cells 02/2015; 33(6). DOI:10.1002/stem.1968 · 7.70 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Temporal lobe epilepsy (TLE) is a common epilepsy syndrome with a complex etiology. Despite evidence for the participation of genetic factors, the genetic basis of TLE remains largely unknown. A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago. However, until now there was no report of pathogenic mutations in GAL, the galanin-encoding gene, and therefore its role in human epilepsy was not established. Here, we studied a family with a pair of monozygotic twins affected by TLE and two unaffected siblings born to healthy parents. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE. In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE. The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the temporal lobe epilepsy in this family. Given the availability of galanin agonists which inhibit seizures, our findings could potentially have direct implications for the development of anti-epileptic treatment.
    Human Molecular Genetics 02/2015; · 6.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Temporal lobe epilepsy (TLE) is a common epilepsy syndrome with a complex etiology. Despite evidence for the participation of genetic factors, the genetic basis of TLE remains largely unknown. A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago. However, until now there was no report of pathogenic mutations in GAL, the galanin-encoding gene, and therefore its role in human epilepsy was not established. Here, we studied a family with a pair of monozygotic twins affected by TLE and two unaffected siblings born to healthy parents. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE. In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE. The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the temporal lobe epilepsy in this family. Given the availability of galanin agonists which inhibit seizures, our findings could potentially have direct implications for the development of anti-epileptic treatment. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 02/2015; 24(11). DOI:10.1093/hmg/ddv060 · 6.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital heart defects (CHD) occur in approximately 50% of patients with Down syndrome (DS); the mechanisms for this occurrence however remain unknown. In order to understand how these defects evolve in early development in Down syndrome, we focused on the earliest stages of cardiogenesis to ascertain perturbations in development leading to CHD. Using a trisomy 21 (T21) sibling human embryonic stem cell (hESC) model of DS, we show that T21-hESC display many significant differences in expression of genes and cell populations associated with mesodermal, and more notably, secondary heart field (SHF) development, in particular a reduced number of ISL1+ progenitor cells. Furthermore, we provide evidence for two candidate genes located on chromosome 21, ETS2 and ERG, whose overexpression during cardiac commitment likely account for the disruption of SHF development, as revealed by down regulation or overexpression experiments. Additionally, we uncover an abnormal electrophysiological phenotype in functional T21-cardiomyocytes, a result further supported by mRNA expression data acquired using RNA-Seq. These data, in combination, revealed a cardiomyocyte-specific phenotype in T21-cardiomyocytes, likely due to the overexpression of genes such as RYR2, NCX and L-type Ca2+ channel. These results contribute to the understanding of the mechanisms involved in the development of CHD. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The trisomy of human chromosome 21 (Hsa21), which causes Down syndrome (DS), is the most common viable human aneuploidy. In contrast to trisomy, the complete monosomy (M21) of Hsa21 is lethal, and only partial monosomy or mosaic monosomy of Hsa21 is seen. Both conditions lead to variable physiological abnormalities with constant intellectual disability, locomotor deficits, and altered muscle tone. To search for dosage-sensitive genes involved in DS and M21 phenotypes, we created two new mouse models: the Ts3Yah carrying a tandem duplication and the Ms3Yah carrying a deletion of the Hspa13-App interval syntenic with 21q11.2-q21.3. Here we report that the trisomy and the monosomy of this region alter locomotion, muscle strength, mass, and energetic balance. The expression profiling of skeletal muscles revealed global changes in the regulation of genes implicated in energetic metabolism, mitochondrial activity, and biogenesis. These genes are downregulated in Ts3Yah mice and upregulated in Ms3Yah mice. The shift in skeletal muscle metabolism correlates with a change in mitochondrial proliferation without an alteration in the respiratory function. However, the reactive oxygen species (ROS) production from mitochondrial complex I decreased in Ms3Yah mice, while the membrane permeability of Ts3Yah mitochondria slightly increased. Thus, we demonstrated how the Hspa13-App interval controls metabolic and mitochondrial phenotypes in muscles certainly as a consequence of change in dose of Gabpa, Nrip1, and Atp5j. Our results indicate that the copy number variation in the Hspa13-App region has a peripheral impact on locomotor activity by altering muscle function.
    PLoS Genetics 02/2015; 11(3):e1005062. DOI:10.1371/journal.pgen.1005062 · 8.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Understanding how genetic variation affects distinct cellular phenotypes, such as gene expression levels, alternative splicing and DNA methylation levels, is essential for better understanding of complex diseases and traits. Furthermore, how inter-individual variation of DNA methylation is associated to gene expression is just starting to be studied. In this study, we use the GenCord cohort of 204 newborn Europeans' lymphoblastoid cell lines, T-cells and fibroblasts derived from umbilical cords. The samples were previously genotyped for 2.5 million SNPs, mRNA-sequenced, and assayed for methylation levels in 482,421 CpG sites. We observe that methylation sites associated to expression levels are enriched in enhancers, gene bodies and CpG island shores. We show that while the correlation between DNA methylation and gene expression can be positive or negative, it is very consistent across cell-types. However, this epigenetic association to gene expression appears more tissue-specific than the genetic effects on gene expression or DNA methylation (observed in both sharing estimations based on P-values and effect size correlations between cell-types). This predominance of genetic effects can also be reflected by the observation that allele specific expression differences between individuals dominate over tissue-specific effects. Additionally, we discover genetic effects on alternative splicing and interestingly, a large amount of DNA methylation correlating to alternative splicing, both in a tissue-specific manner. The locations of the SNPs and methylation sites involved in these associations highlight the participation of promoter proximal and distant regulatory regions on alternative splicing. Overall, our results provide high-resolution analyses showing how genome sequence variation has a broad effect on cellular phenotypes across cell-types, whereas epigenetic factors provide a secondary layer of variation that is more tissue-specific. Furthermore, the details of how this tissue-specificity may vary across inter-relations of molecular traits, and where these are occurring, can yield further insights into gene regulation and cellular biology as a whole.
    PLoS Genetics 02/2015; 11(1):e1004958. DOI:10.1371/journal.pgen.1004958 · 8.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital heart defects (CHD) occur in approximately 50% of patients with Down syndrome (DS); the mechanisms for this occurrence however remain unknown. In order to understand how these defects evolve in early development in Down syndrome, we focused on the earliest stages of cardiogenesis to ascertain perturbations in development leading to CHD. Using a trisomy 21 (T21) sibling human embryonic stem cell (hESC) model of DS, we show that T21-hESC display many significant differences in expression of genes and cell populations associated with mesodermal, and more notably, secondary heart field (SHF) development, in particular a reduced number of ISL1+ progenitor cells. Furthermore, we provide evidence for two candidate genes located on chromosome 21, ETS2 and ERG, whose overexpression during cardiac commitment likely account for the disruption of SHF development, as revealed by down regulation or overexpression experiments. Additionally, we uncover an abnormal electrophysiological phenotype in functional T21-cardiomyocytes, a result further supported by mRNA expression data acquired using RNA-Seq. These data, in combination, revealed a cardiomyocyte-specific phenotype in T21-cardiomyocytes, likely due to the overexpression of genes such as RYR2, NCX and L-type Ca2+ channel. These results contribute to the understanding of the mechanisms involved in the development of CHD. This article is protected by copyright. All rights reserved.
    Stem Cells 01/2015; 33(5). DOI:10.1002/stem.1961 · 7.70 Impact Factor
  • Source
    01/2015; 4(1):18-23. DOI:10.1097/01.MXE.0000457060.97665.02
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The study of gene expression in mammalian single cells via genomic technologies now provides the possibility to investigate the patterns of allelic gene expression. We used single-cell RNA sequencing to detect the allele-specific mRNA level in 203 single human primary fibroblasts over 133,633 unique heterozygous single-nucleotide variants (hetSNVs). We observed that at the snapshot of analyses, each cell contained mostly transcripts from one allele from the majority of genes; indeed, 76.4% of the hetSNVs displayed stochastic monoallelic expression in single cells. Remarkably, adjacent hetSNVs exhibited a haplotype-consistent allelic ratio; in contrast, distant sites located in two different genes were independent of the haplotype structure. Moreover, the allele-specific expression in single cells correlated with the abundance of the cellular transcript. We observed that genes expressing both alleles in the majority of the single cells at a given time point were rare and enriched with highly expressed genes. The relative abundance of each allele in a cell was controlled by some regulatory mechanisms given that we observed related single-cell allelic profiles according to genes. Overall, these results have direct implications in cellular phenotypic variability.
    The American Journal of Human Genetics 12/2014; DOI:10.1016/j.ajhg.2014.12.001 · 10.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Inherited thrombocytopenias (IT) are a heterogeneous group of rare diseases characterized by a reduced number of blood platelets. The frequency of IT is probably underestimated because of diagnostic difficulties and because not all the existing forms have as yet been identified, with some patients remaining without a definitive diagnosis. Exome Sequencing has made possible the identification of almost all variants in the coding regions of protein-coding genes, thereby providing the opportunity to identify the disease causing gene in a number of patients with indefinite diagnoses, specifically in consanguineous families.Case presentationFamilial thrombocytopenia with small size platelets was present in several members of a highly consanguineous family from Northern Iraq. Genotyping of all affected, their unaffected siblings and parents, followed by exome sequencing revealed a strong candidate loss of function variant in a homozygous state: a frameshift mutation in the FYB gene. The protein encoded by this gene is known to be a cytosolic adaptor molecule expressed by T, natural killer (NK), myeloid cells and platelets, and is involved in platelet activation and controls the expression of interleukin-2. Knock-out mice were reported to show isolated thrombocytopenia.Conclusion Inherited thrombocytopenias differ in their presentation, associated features, and molecular etiologies. An accurate diagnosis is needed to provide appropriate management as well as counseling for the individuals and their family members. Exome sequencing may become a first diagnostic tool to identify the molecular basis of undiagnosed familial IT. In this report, the clinical evaluation combined with the power and efficiency of genomic analysis defined the FYB gene as the possible underlying cause of autosomal recessive thrombocytopenia with small platelet size. This is the first report linking pathogenic variants in FYB and thrombocytopenia in humans.
    BMC Medical Genetics 12/2014; 15(1):135. DOI:10.1186/s12881-014-0135-0 · 2.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alteration of the number of copies of double minutes (DMs) with oncogenic EGFR mutations in response to tyrosine kinase inhibitors is a novel adaptive mechanism of glioblastoma. Here we provide evidence that such mutations in DMs, called here amplification-linked extrachromosomal mutations (ALEMs), originate extrachromosomally and could therefore be completely eliminated from the cancer cells. By exome sequencing of seven glioblastoma patients we reveal ALEMs in EGFR, PDGFRA and other genes. These mutations together with DMs are lost by cancer cells in culture. We confirm the extrachromosomal origin of such mutations by showing that wild-type and mutated DMs may coexist in the same tumour. Analysis of 4,198 tumours suggests the presence of ALEMs across different tumour types with the highest prevalence in glioblastomas and low-grade gliomas. The extrachromosomal nature of ALEMs explains the observed drastic changes in the amounts of mutated oncogenes (like EGFR or PDGFRA) in glioblastoma in response to environmental changes.
    Nature Communications 12/2014; 5. DOI:10.1038/ncomms6690 · 10.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gene expression levels can be subject to selection. We hypothesized that the age of gene origin is associated with expression constraints, given that it affects the level of gene integration into the functional cellular environment. By studying the genetic variation affecting gene expression levels (cis expression quantitative trait loci [cis-eQTLs]) and protein levels (cis protein QTLs [cis-pQTLs]), we determined that young, primate-specific genes are enriched in cis-eQTLs and cis-pQTLs. Compared to cis-eQTLs of old genes originating before the zebrafish divergence, cis-eQTLs of young genes have a higher effect size, are located closer to the transcription start site, are more significant, and tend to influence genes in multiple tissues and populations. These results suggest that the expression constraint of each gene increases throughout its lifespan. We also detected a positive correlation between expression constraints (approximated by cis-eQTL properties) and coding constraints (approximated by Ka/Ks) and observed that this correlation might be driven by gene age. To uncover factors associated with the increase in gene-age-related expression constraints, we demonstrated that gene connectivity, gene involvement in complex regulatory networks, gene haploinsufficiency, and the strength of posttranscriptional regulation increase with gene age. We also observed an increase in heritability of gene expression levels with age, implying a reduction of the environmental component. In summary, we show that gene age shapes key gene properties during evolution and is therefore an important component of genome function. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 12/2014; 95(6):660-74. DOI:10.1016/j.ajhg.2014.11.003 · 10.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia (SCZ) is a severe, debilitating mental illness which has a significant genetic component. The identification of genetic factors related to SCZ has been challenging and these factors remain largely unknown. To evaluate the contribution of de novo variants (DNVs) to SCZ, we sequenced the exomes of 53 individuals with sporadic SCZ and of their non-affected parents. We identified 49 DNVs, 18 of which were predicted to alter gene function, including 13 damaging missense mutations, 2 conserved splice site mutations, 2 nonsense mutations, and 1 frameshift deletion. The average number of exonic DNV per proband was 0.88, which corresponds to an exonic point mutation rate of 1.7×10−8 per nucleotide per generation. The non-synonymous-to-synonymous mutation ratio of 2.06 did not differ from neutral expectations. Overall, this study provides a list of 18 putative candidate genes for sporadic SCZ, and when combined with the results of similar reports, identifies a second proband carrying a non-synonymous DNV in the RGS12 gene.
    PLoS ONE 11/2014; DOI:10.1371/journal.pone.0112745 · 3.53 Impact Factor

Publication Stats

48k Citations
6,092.06 Total Impact Points

Institutions

  • 1993–2015
    • University of Geneva
      • • Department of Genetic Medicine and Development (GEDEV)
      • • University Centre for Informatics
      Genève, Geneva, Switzerland
  • 2014
    • Institut Clinique de la Souris
      Illkirch, Alsace, France
  • 2013
    • Radboud University Nijmegen
      • Institute for Genetic and Metabolic Disease
      Nymegen, Gelderland, Netherlands
    • Geneva College
      Женева, Illinois, United States
  • 2012
    • Institute of Genetics & Hospital for Genetic Diseases
      Bhaganagar, Telangana, India
  • 2009
    • University of Patras
      Rhion, West Greece, Greece
  • 2008
    • Academy of Athens
      Athínai, Attica, Greece
  • 2006–2008
    • University of Lausanne
      • • Institute of Microbiology
      • • Center for Integrative Genomics (CIG)
      Lausanne, Vaud, Switzerland
  • 2007
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
    • United Arab Emirates University
      Al Ain, Abu Dhabi, United Arab Emirates
  • 2005–2006
    • Wellcome Trust Sanger Institute
      • Cancer Genome Project
      Cambridge, England, United Kingdom
  • 1982–2005
    • Johns Hopkins University
      • Department of Pediatrics
      Baltimore, MD, United States
  • 2001–2004
    • Hôpitaux Universitaires de Genève
      Genève, Geneva, Switzerland
    • University of Hamburg
      Hamburg, Hamburg, Germany
    • University of Washington Seattle
      Seattle, Washington, United States
    • Stanford Medicine
      Stanford, California, United States
    • Centre universitaire romand de médecine légale Lausanne - Genève (CURML)
      Genève, Geneva, Switzerland
  • 2003
    • Leiden University Medical Centre
      Leyden, South Holland, Netherlands
  • 1987–2003
    • Yale University
      • School of Medicine
      New Haven, Connecticut, United States
  • 2002
    • The University of Western Ontario
      • Department of Computer Science
      London, Ontario, Canada
  • 2000–2002
    • Stanford University
      • Department of Psychiatry and Behavioral Sciences
      Palo Alto, California, United States
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 1996–2001
    • Cantonal Hospital of Schwyz
      Schwyz, Schwyz, Switzerland
    • The Rockefeller University
      New York City, New York, United States
  • 1999
    • University of Cambridge
      Cambridge, England, United Kingdom
    • University of Oulu
      Uleoborg, Oulu, Finland
    • Keio University
      • Department of Molecular Biology
      Edo, Tōkyō, Japan
  • 1998
    • Columbia University
      New York, New York, United States
  • 1997
    • Case Western Reserve University
      Cleveland, Ohio, United States
  • 1995
    • Baylor College of Medicine
      • Department of Molecular & Human Genetics
      Houston, Texas, United States
  • 1994
    • University of Maryland, Baltimore
      • Department of Pediatrics
      Baltimore, MD, United States
  • 1987–1994
    • Johns Hopkins Medicine
      • Department of Pediatrics
      Baltimore, Maryland, United States
  • 1984–1994
    • University of Pittsburgh
      • • Department of Human Genetics
      • • Department of Biostatistics
      Pittsburgh, Pennsylvania, United States
  • 1991
    • University of Zurich
      Zürich, Zurich, Switzerland
  • 1990
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 1988
    • New York State Institute for Basic Research in Developmental Disabilities
      New York, New York, United States
    • Peking Union Medical College Hospital
      Peping, Beijing, China
  • 1986
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1985
    • National Institutes of Health
      • Chemical Biology Laboratory
      베서스다, Maryland, United States