Stylianos E. Antonarakis

University of Geneva, Genève, Geneva, Switzerland

Are you Stylianos E. Antonarakis?

Claim your profile

Publications (778)6215.1 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: APOBEC3A and APOBEC3B, cytidine deaminases of the APOBEC family, are among the main factors causing mutations in human cancers. APOBEC deaminates cytosines in single-stranded DNA (ssDNA). A fraction of the APOBEC-induced mutations occur as clusters ("kataegis") in single-stranded DNA produced during repair of double-stranded breaks (DSBs). However, the properties of the remaining 87% of nonclustered APOBEC-induced mutations, the source and the genomic distribution of the ssDNA where they occur, are largely unknown. By analyzing genomic and exomic cancer databases, we show that >33% of dispersed APOBEC-induced mutations occur on the lagging strand during DNA replication, thus unraveling the major source of ssDNA targeted by APOBEC in cancer. Although methylated cytosine is generally more mutation-prone than nonmethylated cytosine, we report that methylation reduces the rate of APOBEC-induced mutations by a factor of roughly two. Finally, we show that in cancers with extensive APOBEC-induced mutagenesis, there is almost no increase in mutation rates in late replicating regions (contrary to other cancers). Because late-replicating regions are depleted in exons, this results in a 1.3-fold higher fraction of mutations residing within exons in such cancers. This study provides novel insight into the APOBEC-induced mutagenesis and describes the peculiarity of the mutational processes in cancers with the signature of APOBEC-induced mutations.
    Full-text · Article · Jan 2016 · Genome Research
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The genetic program, as manifested as the cellular phenotype, is in large part dictated by the cell’s protein composition. Since characterisation of the proteome remains technically laborious it is attractive to define the genetic expression profile using the transcriptome. However, the transcriptional landscape is complex and it is unclear as to what extent it reflects the ribosome associated mRNA population (the translatome). This is particularly pertinent for genes using multiple transcriptional start sites (TSS) generating mRNAs with heterogeneous 5′ transcript leaders (5′TL). Furthermore, the relative abundance of the TSS gene variants is frequently cell-type specific. Indeed, promoter switches have been reported in pathologies such as cancer. The consequences of this 5′TL heterogeneity within the transcriptome for the translatome remain unresolved. This is not a moot point because the 5′TL plays a key role in regulating mRNA recruitment onto polysomes. In this article, we have characterised both the transcriptome and translatome of the MCF7 (tumoural) and MCF10A (non-tumoural) cell lines. We identified ~550 genes exhibiting differential translation efficiency (TE). In itself, this is maybe not surprising. However, by focusing on genes exhibiting TSS heterogeneity we observed distinct differential promoter usage patterns in both the transcriptome and translatome. Only a minor fraction of these genes belonged to those exhibiting differential TE. Nonetheless, reporter assays demonstrated that the TSS variants impacted on the translational readout both quantitatively (the overall amount of protein expressed) and qualitatively (the nature of the proteins expressed). The results point to considerable and distinct cell-specific 5′TL heterogeneity within both the transcriptome and translatome of the two cell lines analysed. This observation is in-line with the ribosome filter hypothesis which posits that the ribosomal machine can selectively filter information from within the transcriptome. As such it cautions against the simple extrapolation transcriptome → proteome. Furthermore, polysomal occupancy of specific gene 5′TL variants may also serve as novel disease biomarkers.
    Full-text · Article · Dec 2015 · BMC Genomics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We report the case of a female patient suffering from a 46,XY disorder of sexual development (DSD) with complete gonadal dysgenesis and Wiedemann-Steiner Syndrome (WDSTS). The coexistence of these 2 conditions has not yet been reported. Using whole exome sequencing and comparative genome hybridization array, we identified a de novo MLL/KMT2A gene nonsense mutation which explains the WDSTS phenotype. In addition, we discovered novel genetic variants, which could explain the testicular dysgenesis observed in the patient, a maternally inherited 167-kb duplication of DAAM2 and MOCS1 genes and a de novo LRRC33/NRROS gene mutation. These genes, some of which are expressed during mouse gonadal development, could be considered as potentially new candidate genes for DSD.
    Full-text · Article · Nov 2015 · Sexual Development
  • Source

    Full-text · Article · Nov 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: HIV-1 Nef, a protein important for the development of AIDS, has well-characterized effects on host membrane trafficking and receptor downregulation. By an unidentified mechanism, Nef increases the intrinsic infectivity of HIV-1 virions in a host-cell-dependent manner. Here we identify the host transmembrane protein SERINC5, and to a lesser extent SERINC3, as a potent inhibitor of HIV-1 particle infectivity that is counteracted by Nef. SERINC5 localizes to the plasma membrane, where it is efficiently incorporated into budding HIV-1 virions and impairs subsequent virion penetration of susceptible target cells. Nef redirects SERINC5 to a Rab7-positive endosomal compartment and thereby excludes it from HIV-1 particles. The ability to counteract SERINC5 was conserved in Nef encoded by diverse primate immunodeficiency viruses, as well as in the structurally unrelated glycosylated Gag from murine leukaemia virus. These examples of functional conservation and convergent evolution emphasize the fundamental importance of SERINC5 as a potent anti-retroviral factor.
    No preview · Article · Sep 2015 · Nature
  • Source
    Federico Andrea Santoni · Periklis Makrythanasis · Stylianos E. Antonarakis
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Consanguinity is an important risk factor for autosomal recessive (AR) disorders. Extended genomic regions identical by descent (IBD) in the offspring of consanguineous parents give rise to recessive disorders with identical (homozygous) pathogenic variants in both alleles. However, many clinical phenotypes presenting in the offspring of consanguineous couples are still of unknown etiology. Nowadays advances in High Throughput Sequencing provide an excellent opportunity to achieve a molecular diagnosis or to identify novel candidate genes. Results To exploit all available information from the family structure we developed CATCH, an algorithm that combines genotyped SNPs of all family members for the optimal detection of Runs Of Homozygosity (ROH) and exome sequencing data from one affected individual to identify putative causative variants in consanguineous families. Conclusions CATCH proved to be effective in discovering known or putative new causative variants in 43 out of 50 consanguineous families. Among them, novel variants causative of familial thrombocytopenia, sclerosis bone dysplasia and the first homozygous loss-of-function mutation in FGFR3 in human causing severe skeletal deformities, tall stature and hearing impairment were identified.
    Full-text · Article · Sep 2015 · BMC Bioinformatics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: DNA methylation is essential in mammalian development. We have hypothesized that methylation differences induced by trisomy 21 (T21) contribute to the phenotypic characteristics and heterogeneity in Down syndrome (DS). In order to determine the methylation differences in T21 without interference of the interindividual genomic variation, we have used fetal skin fibroblasts from monozygotic (MZ) twins discordant for T21. We also used skin fibroblasts from MZ twins concordant for T21, normal MZ twins without T21, and unrelated normal and T21 individuals. Reduced Representation Bisulfite Sequencing (RRBS) revealed 35 differentially methylated promoter regions (DMRs) (Absolute methylation differences = 25%, FDR < 0.001) in MZ twins discordant for T21 that have also been observed in comparison between unrelated normal and T21 individuals. The identified DMRs are enriched for genes involved in embryonic organ morphogenesis (FDR = 1.60 e -03) and include genes of the HOXB and HOXD clusters. These DMRs are maintained in iPS cells generated from this twin pair and are correlated with the gene expression changes. We have also observed an increase in DNA methylation level in the T21 methylome compared to the normal euploid methylome. This observation is concordant with the up regulation of DNA methyltransferase enzymes (DNMT3B and DNMT3L) and down regulation of DNA demethylation enzymes (TET2 and TET3) observed in the iPSC of the T21 versus normal twin. Altogether, the results of this study highlight the epigenetic effects of the extra chromosome 21 in T21 on loci outside of this chromosome that are relevant to DS associated phenotypes.
    Full-text · Article · Aug 2015 · PLoS ONE
  • Source
    Dataset: 2011 JBC-SM

    Full-text · Dataset · Jul 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: To document the clinical characteristics and inheritance pattern of epilepsy in multigeneration Algerian families. Methods: Affected members from extended families with familial epilepsy were assessed at the University Hospital of Oran in Algeria. Available medical records, neurological examination, electroencephalography and imaging data were reviewed. The epilepsy type was classified according to the criteria of the International League Against Epilepsy and modes of inheritance were deduced from pedigree analysis. Results: The study population included 40 probands; 23 male (57.5%) and 17 female subjects (42.5%). The mean age of seizure onset was 9.5±6.1 years. According to seizure onset, 16 patients (40%) had focal seizures and 20 (50%) had generalized seizures. Seizure control was achieved for two patients (5%) for 10 years, while 28 (70%) were seizure-free for 3 months. Eleven patients (27.5%) had prior febrile seizures, 12 were diagnosed with psychiatric disorders and four families had syndromic epilepsy. The consanguinity rate among parents of affected was 50% with phenotypic concordance observed in 25 families (62.5%). Pedigree analysis suggested autosomal dominant (AD) inheritance with or without reduced penetrance in 18 families (45%), probable autosomal recessive (AR) inheritance in 14 families (35%), and an X-linked recessive inheritance in one family. Conclusion: This study reveals large Algerian families with multigenerational inheritance of epilepsy. Molecular testing such as exome sequencing would clarify the genetic basis of epilepsy in some of our families.
    Full-text · Article · Jul 2015 · Seizure
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The HSA21 encoded Single-minded 2 (SIM2) transcription factor has key neurological functions and is a good candidate to be involved in the cognitive impairment of Down syndrome. We aimed to explore the functional capacity of SIM2 by mapping its DNA binding sites in mouse embryonic stem cells. ChIP-sequencing revealed 1229 high-confidence SIM2-binding sites. Analysis of the SIM2 target genes confirmed the importance of SIM2 in developmental and neuronal processes and indicated that SIM2 may be a master transcription regulator. Indeed, SIM2 DNA binding sites share sequence specificity and overlapping domains of occupancy with master transcription factors such as SOX2, OCT4 (Pou5f1), NANOG or KLF4. The association between SIM2 and these pioneer factors is supported by co-immunoprecipitation of SIM2 with SOX2, OCT4, NANOG or KLF4. Furthermore, the binding of SIM2 marks a particular sub-category of enhancers known as super-enhancers. These regions are characterized by typical DNA modifications and Mediator co-occupancy (MED1 and MED12). Altogether, we provide evidence that SIM2 binds a specific set of enhancer elements thus explaining how SIM2 can regulate its gene network in neuronal features.
    Full-text · Article · May 2015 · PLoS ONE

  • No preview · Article · May 2015 · Acta Physiologica
  • 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.
    Full-text · Article · Apr 2015 · Genome Research
  • 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
    Full-text · Article · Mar 2015 · PLoS Genetics
  • A. Dahdouh Guermouche · M. Guipponi · J. Prados · S. Antonarakis

    No preview · Article · Mar 2015 · European Psychiatry
  • 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.
    Full-text · Article · Feb 2015 · Human Molecular Genetics
  • 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.
    Full-text · Article · Feb 2015 · Human Molecular Genetics
  • 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.
    Full-text · Article · Feb 2015 · Stem Cells
  • [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.
    No preview · Article · Feb 2015 · Human Molecular Genetics
  • Source
    [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.
    Full-text · Article · Feb 2015 · Human Molecular Genetics
  • 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.
    Full-text · Dataset · Feb 2015

Publication Stats

57k Citations
6,215.10 Total Impact Points

Institutions

  • 1993-2015
    • University of Geneva
      • Department of Genetic Medicine and Development (GEDEV)
      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
  • 2010
    • National Centre of Competence in Research LIVES
      Lausanne, Vaud, Switzerland
    • Swiss Institute of Bioinformatics
      Lausanne, Vaud, Switzerland
  • 2009
    • University of Patras
      Rhion, West Greece, Greece
  • 2008
    • Academy of Athens
      Athínai, Attica, Greece
  • 2007
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
  • 2006
    • University of California, San Francisco
      • Department of Pediatrics
      San Francisco, California, United States
    • University Pompeu Fabra
      • Center for Genomic Regulation (CRG)
      Barcino, Catalonia, Spain
  • 2005-2006
    • Wellcome Trust Sanger Institute
      • Cancer Genome Project
      Cambridge, England, United Kingdom
  • 1982-2005
    • Johns Hopkins University
      • • Department of Pediatrics
      • • Department of Medicine
      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
    • Centre universitaire romand de médecine légale Lausanne - Genève (CURML)
      Genève, Geneva, Switzerland
  • 2003
    • Leiden University Medical Centre
      • Department of Human Genetics
      Leyden, South Holland, Netherlands
  • 2002
    • The University of Western Ontario
      • Department of Computer Science
      London, Ontario, Canada
  • 2001-2002
    • Stanford University
      • Department of Psychiatry and Behavioral Sciences
      Palo Alto, California, United States
  • 1998-2002
    • Columbia University
      New York, New York, United States
  • 1996-2001
    • Cantonal Hospital of Schwyz
      Schwyz, Schwyz, Switzerland
  • 2000
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 1999
    • MRC Clinical Sciences Centre
      London Borough of Harrow, England, United Kingdom
    • University of Cambridge
      Cambridge, England, United Kingdom
    • Keio University
      • Department of Molecular Biology
      Edo, Tōkyō, Japan
    • University of Oulu
      Uleoborg, Oulu, Finland
  • 1997
    • Case Western Reserve University
      Cleveland, Ohio, United States
  • 1985-1995
    • Baylor College of Medicine
      • Department of Molecular & Human Genetics
      Houston, Texas, United States
    • National Institutes of Health
      • Chemical Biology Laboratory
      베서스다, Maryland, United States
  • 1987-1994
    • Johns Hopkins Medicine
      • Department of Pediatrics
      Baltimore, Maryland, United States
    • Yale University
      • School of Medicine
      New Haven, Connecticut, 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
  • 1989
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 1988
    • New York State Institute for Basic Research in Developmental Disabilities
      New York, New York, United States
    • Weizmann Institute of Science
      Rhovot, Central District, Israel
    • Peking Union Medical College Hospital
      Peping, Beijing, China
  • 1986
    • Harvard University
      Cambridge, Massachusetts, United States
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1984-1986
    • Boston Children's Hospital
      Boston, Massachusetts, United States