M L Yaspo

Max Planck Institute for Molecular Genetics, Berlín, Berlin, Germany

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Publications (26)186.73 Total impact

  • Nucleic Acids Research 06/2014; 42(14):e110.. · 8.81 Impact Factor
  • Cold Spring Harbor Symposia on Quantitative Biology 02/2003; 68:455-60.
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    M L Yaspo
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    ABSTRACT: The elucidation of genetic components of human diseases at the molecular level provides crucial information for developing future causal therapeutic intervention. High-throughput genome sequencing and systematic experimental approaches are fuelling strategic programs designed to investigate gene function at the biochemical, cellular and organism levels. Bioinformatics is one important tool in functional genomics, although showing clear limitations in predicting ab initio gene structures, gene function and protein folds from raw sequence data. Systematic large-scale data-set generation, using the same type of experiments that are used to decipher the function of single genes, are being applied on entire genomes. Comparative genomics, establishment of gene catalogues, and investigation of cellular and tissue molecular profiles are providing essential tools for understanding gene function in complex biological networks.
    Trends in Molecular Medicine 12/2001; 7(11):494-501. · 9.57 Impact Factor
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    M L Yaspo
    Dialogues in clinical neuroscience 03/2001; 3(1):58-61.
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    ABSTRACT: The testis-expressed human TPTE is a putative transmembrane tyrosine phosphatase, probably involved in signal transduction pathways of the endocrine and/or the spermatogenetic function of the testis. TPTE was mapped to the pericentromeric region of human chromosomes 21 and 13, and to chromosomes 15, 22, and Y. It is unknown which of the TPTE copies are transcribed, contain intronic sequences, and/or have open reading frames. Here, in silico analysis of the genomic sequence of human chromosome 21 allowed the determination of the genomic structure of a copy of the TPTE gene. This copy consists of 24 exons and spans approximately 87 kb. The mapping position of this copy of TPTE on the short arm of chromosome 21 was confirmed by FISH using the BAC 15L0C0 clone as a probe that contains almost the entire TPTE gene. This is the first description of the genomic sequence of a non-RNR gene on the short arm of human acrocentric chromosomes.
    Human Genetics 09/2000; 107(2):127-31. · 4.63 Impact Factor
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    ABSTRACT: Chromosome 21 is the smallest human autosome. An extra copy of chromosome 21 causes Down syndrome, the most frequent genetic cause of significant mental retardation, which affects up to 1 in 700 live births. Several anonymous loci for monogenic disorders and predispositions for common complex disorders have also been mapped to this chromosome, and loss of heterozygosity has been observed in regions associated with solid tumours. Here we report the sequence and gene catalogue of the long arm of chromosome 21. We have sequenced 33,546,361 base pairs (bp) of DNA with very high accuracy, the largest contig being 25,491,867 bp. Only three small clone gaps and seven sequencing gaps remain, comprising about 100 kilobases. Thus, we achieved 99.7% coverage of 21q. We also sequenced 281,116 bp from the short arm. The structural features identified include duplications that are probably involved in chromosomal abnormalities and repeat structures in the telomeric and pericentromeric regions. Analysis of the chromosome revealed 127 known genes, 98 predicted genes and 59 pseudogenes.
    Nature 06/2000; 405(6784):311-9. · 38.60 Impact Factor
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    ABSTRACT: To establish criteria for and the limitations of novel gene identification, to identify novel genes of potential relevance to Down Syndrome and to investigate features of genome organization, 6. 550kb. In total, 41 novel gene models were predicted, and for a subset of these, RT-PCR experiments helped to verify and refine the models, and were used to assess expression in early development and in adult brain regions of potential relevance to Down syndrome. Results suggest generally low and/or restricted patterns of expression, and also reveal examples of complex alternative processing, especially in brain, that may have important implications for regulation of protein function. Analysis of complete gene structures of the known genes identified a number of very large introns, a number of very short intergenic distances, and at least one potentially bi-directional promoter. At least 3/4 of known genes and 1/2 of predicted genes are associated with CpG islands. For novel genes, three cases of overlapping genes are predicted. Results of these analyses illustrate some of the complexities inherent in mammalian genome organization and some of the limitations of current sequence analysis technologies. They also doubled the number of potential genes within the region.
    Gene 05/2000; 247(1-2):215-32. · 2.20 Impact Factor
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    ABSTRACT: The chromosomal abnormality represented by an isodicentric X chromosome [idic(X)(q13)] is associated with a subset of acute myeloid leukemia (AML) and preleukemia observed in elderly females. A previous study localized the breakpoints of two acquired isodicentric X chromosomes associated with myelodysplasia to a 450-kb region proximal to the XIST gene. Here we report the construction and extensive characterization of a reliable 1-Mb P1 artificial chromosome and bacterial artificial chromosome contig covering a highly problematic region in Xq13 that includes the previously described isodicentric breakpoint region. In addition to mapping of the brain-specific gene (NAP1L2) and the phosphoglyceryl kinase alpha subunit 1 gene (PHKA1) and generation and mapping of a large number of STSs throughout the contig, we have mapped a putative transcriptional regulatory protein (HDACL1), and 35 ESTs. Sequencing data, Southern blot analysis, and fiber-FISH analysis have permitted characterization of extensive region-specific duplications and triplications in addition to an unusually high concentration of long interspersed repeat elements, both of which could be implicated in isodicentric chromosome formation and other Xq13 chromosome aberrations. FISH analysis of metaphase chromosomes from two previously unpublished AML patients and one preleukemic patient using cosmid clones and selected subclones allowed mapping of the idic(X)(q13) breakpoints to a 100-kb interval, consistent with the involvement of an X-linked gene in the genesis of this form of preleukemia, disruption of which may represent a preliminary step in progression to AML. Assembly and physical mapping of this complex 1-Mb contig establish a foundation for ongoing sequencing and gene identification projects in the region.
    Genomics 04/2000; 64(3):221-9. · 3.01 Impact Factor
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    ABSTRACT: Phenotypic and molecular analyses of patients with partial chromosome 21 monosomy enabled us to define a region, spanning 2.4 Mb between D21S190 and D21S226, associated with arthrogryposis, mental retardation, hypertonia, and several facial anomalies. The markers of the region were used to screen a total human PAC library (Ioannou, RZPD). We isolated 57 PACs, which formed primary contigs. EST clusters (UNIGENE collection) located in a 6-Mb interval, between D21S260 and D21S263, were mapped in individual bacterial clones. We mapped the WI-17843 cluster to the PAC clone J12100, which contains the two anchor markers LB10T and LA329. The open reading frame extends over 960 bp, with three putative start codons. The 1695-bp cDNA containing a polyadenylation signal should correspond to the full-length cDNA. From the genomic sequence, we deduced that the gene contained five exons and that there was a putative promoter sequence upstream from exon 1. In silico screening of DNA databases revealed similarity with a murine EST. The corresponding cDNA (1757 bp) sequence was very similar (>85%) to the human cDNA and had an open reading frame of 876 nucleotides. Somatic hybrid mapping localized the cDNA to mouse chromosome 16. EST analyses and RT-PCR indicated that the third exon in the human gene (exon 2 in the mouse) undergoes alternative splicing. Northern blot hybridization showed that the gene was ubiquitously expressed in humans and mice. The longest mouse clone was used to generate riboprobes, which were hybridized to murine embryos at stages E-9.5, E-10.5, E-12.5, E-13.5, and E-14.5-15, to study the pattern of expression during development. Ubiquitous labeling was observed, with strong signals restricted to limited areas of the telencephalon, the mesencephalon, and the interrhombomeric regions in the central nervous system, and other regions of the body such as the limb buds, branchial arches, and somites.
    Genomics 04/2000; 64(2):203-10. · 3.01 Impact Factor
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    ABSTRACT: Progress in complete genomic sequencing of human chromosome 21 relies on the construction of high-quality bacterial clone maps spanning large chromosomal regions. To achieve this goal, we have applied a strategy based on nonradioactive hybridizations to contig building. A contiguous sequence-ready map was constructed in the Down syndrome congenital heart disease (DS-CHD) region in 21q22.2, as a framework for large-scale genomic sequencing and positional candidate gene approach. Contig assembly was performed essentially by high throughput nonisotopic screenings of genomic libraries, prior to clone validation by (1) restriction digest fingerprinting, (2) STS analysis, (3) Southern hybridizations, and (4) FISH analysis. The contig contains a total of 50 STSs, of which 13 were newly isolated. A minimum tiling path (MTP) was subsequently defined that consists of 20 PACs, 2 BACs, and 5 cosmids covering 3 Mb between D21S3 and MX1. Gene distribution in the region includes 9 known genes (c21-LRP, WRB, SH3BGR, HMG14, PCP4, DSCAM, MX2, MX1, and TMPRSS2) and 14 new additional gene signatures consisting of cDNA selection products and ESTs. Forthcoming genomic sequence information will unravel the structural organization of potential candidate genes involved in specific features of Down syndrome pathogenesis.
    Genome Research 05/1999; 9(4):360-72. · 14.40 Impact Factor
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    ABSTRACT: Mutations in the human AIRE gene (hAIRE) result in the development of an autoimmune disease named APECED (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; OMIM 240300). Previously, we have cloned hAIRE and shown that it codes for a putative transcription-associated factor. Here we report the cloning and characterization of Aire, the murine ortholog of hAIRE. Comparative genomic sequencing revealed that the structure of the AIRE gene is highly conserved between human and mouse. The conceptual proteins share 73% homology and feature the same typical functional domains in both species. RT-PCR analysis detected three splice variant isoforms in various mouse tissues, and interestingly one isoform was conserved in human, suggesting potential biological relevance of this product. In situ hybridization on mouse and human histological sections showed that AIRE expression pattern was mainly restricted to a few cells in the thymus, calling for a tissue-specific function of the gene product.
    Genome Research 03/1999; 9(2):158-66. · 14.40 Impact Factor
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    ABSTRACT: A visual transcript map of six genes was constructed on the chromosome 21q22.3 by high resolution fluorescence in situ hybridization (FISH). Expressed sequence tags (ESTs) from six genes-PWP2, KNP1, AIRE, C21orf3, SMT3A, and C21orf1-were successfully localized by fiber-FISH by use of sensitive tyramide-based detection. The sizes of the ESTs varied between 315 to 956 bp and most of them map within the 3'-untranslated region. The ESTs were assigned to and subsequently ordered within cosmid, PAC, and BAC clones hybridized on DNA fibers. Physical distances between ESTs and known markers were determined. Our results demonstrate the feasibility and accuracy of visual mapping EST sequences in relation to known markers. The main advantage of this approach is that it can be applied to finely map any of the database ESTs for positional cloning efforts. The sensitivity, specificity, and reproducibility of this high-resolution EST mapping technique is evaluated.
    Genome Research 02/1999; 9(1):62-71. · 14.40 Impact Factor
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    ABSTRACT: The distal part of human chromosome 21q22.3 is exceptionally gene rich and contains several loci that have been linked to hereditary disorders. In the course of constructing an extensive transcript map for chromosome 21, we have isolated numerous coding segments in 21q22.3 that represent potential candidate genes in this region. Following this approach, we have cloned a novel single-copy gene (C21orf3) (HGMW-approved symbol C21orf1) expressed as a unique 2.69-kb mRNA in a wide range of tissues. We have precisely mapped C21orf3 by fiber FISH distal to marker D21S171. The C21orf3 gene encodes a predicted protein of 180 residues that does not share any sequence homology with other known proteins. C21orf3 harbors predicted structural features of a type Ia integral membrane protein and contains a tetrapeptide motif (YXRF) observed in several cell surface proteins involved in signal transduction. Although the function of C21orf3 is still unknown, this novel gene may play an important role in a cell trafficking mechanism.
    Genomics 05/1998; 49(1):133-6. · 3.01 Impact Factor
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    ABSTRACT: We present a high-resolution bacterial contig map of 3.4 Mb of genomic DNA in human chromosome 21q11-q21, encompassing the region of elevated disomic homozygosity in Down Syndrome-associated abnormal myelopoiesis and leukemia, as well as the markers, which has shown a strong association with Alzheimer's Disease that has never been explained. The map contains 89 overlapping PACs, BACs, or cosmids in three contigs (850, 850, and 1500 kb) with two gaps (one of 140-210 kb and the second <5 kb). To date, eight transcribed sequences derived by cDNA selection, exon trapping, and/or global EST sequencing have been positioned onto the map, and the only two genes so far mapped to this cytogenetic region, STCH and RIP140 have been precisely localized. This work converts a further 10% of chromosome 21q into a high-resolution bacterial contig map, which will be the physical basis for the long-range sequencing of this region. The map will also enable positional derivation of new transcribed sequences, as well as new polymorphic probes, that will help in elucidation of the role the genes in this region may play in abnormal myelopoiesis and leukemia associated with trisomy 21 and Alzheimer's Disease.
    Genome Research 04/1998; 8(4):385-98. · 14.40 Impact Factor
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    ABSTRACT: The molecular background of human autoimmunity is poorly understood. Although many autoimmune diseases have a genetic basis, the actual disease appearance results from a complex interplay between genes and environment and thus these diseases represent typical multifactorial diseases. Even with molecular tools provided by the Human Genome Project, it still remains a challenge to identify the predisposing DNA variants behind such multifactorial traits. Two strategies have been suggested to provide short-cuts to the dissection of the genetic background of complex autoimmune diseases: (i) identification of genes in rare human diseases with a strong autoimmune component or (ii) unravelling loci causing phenotypes resembling autoimmune diseases in inbred mice strains. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autosomal disease with a recessive inheritance pattern, characterized by multiple autoimmune endocrinopathies, chronic mucocutaneous candidiasis and ectodermal dystrophies. Since it is the only known human autoimmune disease inherited in a Mendelian fashion, it provides an excellent model to analyse the genetic component of human autoimmunity. The causative gene for APECED was isolated recently by a traditional positional cloning strategy by two independent groups. The cDNA for the APECED gene proved to originate from a novel gene, AIRE , which is expressed prevalently in thymus, pancreas and adrenal cortex. Multiple mutations in AIRE have been identified in APECED patients. The predicted proline-rich AIRE polypeptide harbours two PHD-type zinc finger motifs and contains a putative nuclear targeting signal suggesting its involvement in the regulation of transcription. In the future, functional analysis of the AIRE protein both in vitro and in vivo will provide valuable insight not only into the molecular pathogenesis of APECED but also into the aetiology of autoimmunity in general.
    Human Molecular Genetics 02/1998; 7(10):1547-53. · 7.69 Impact Factor
  • K Gardiner, M L Yaspo
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    ABSTRACT: The seventh international chromosome 21 workshop was held at the Sorat-Spree Bogen Hotel, Berlin, Germany, on September 12–14, 1997. The meeting was supported by the Deutsches Human Genome Projekt (DHGP; DLR-BMBF) and the Max Planck Institute for Molecular Genetics. Over 70 attendees coming from 14 countries participated in the workshop.
    Cytogenetics and cell genetics 02/1998; 82(1-2):1-12.
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    ABSTRACT: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is the only described systemic autoimmune disease with established monogenic background, and the first autoimmune disorder localized outside the major histocompatibility complex (MHC) region. The primary biochemical defect in APECED is unknown. We have isolated a novel gene, AIRE, encoding for a putative nuclear protein featuring two PHD-type zinc-finger motifs, suggesting its involvement in transcriptional regulation. Five mutations in AIRE are reported in individuals with this disorder. This is the first report of a single-gene defect causing a systemic human autoimmune disease, providing a tool for exploring the molecular basis of autoimmunity.
    Nature Genetics. 11/1997; 17(4):399-403.
  • N Katsanis, M L Yaspo, E M Fisher
    Mammalian Genome 08/1997; 8(7):526-9. · 2.42 Impact Factor
  • Cytogenetics and cell genetics 01/1997; 79(1-2):21-52.
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    ABSTRACT: A new member of the proprotein convertase gene family (LPC) has been identified at a chromosome translocation breakpoint occurring in a high grade lymphoma. The translocation t(11;14)(q23;q32) has been molecularly cloned and shown to be the result of a fusion between an intron in the 3' -untranslated region of LPC with a sequence close to the switch region S gamma 4 of the IGH locus. The LPC gene encodes a protein of 785 amino acids with substantial homology to furin and the other members of the proprotein convertase family and represents a novel target for chromosome translocation and subsequent deregulation.
    Cancer Research 03/1996; 56(3):448-51. · 8.65 Impact Factor

Publication Stats

1k Citations
186.73 Total Impact Points

Institutions

  • 1997–2001
    • Max Planck Institute for Molecular Genetics
      Berlín, Berlin, Germany
    • Cedars-Sinai Medical Center
      Los Angeles, California, United States
  • 2000
    • RIKEN
      Вако, Saitama, Japan